Diphtheria: Clinical Case and Viva QnA

1. Clinical Case of Diphtheria in Children

Patient Presentation

A 4-year-old girl, Mia, is brought to the emergency department by her parents with a 5-day history of worsening symptoms. The family recently returned from a 3-month stay in Southeast Asia, where their vaccination status was unclear.

Chief Complaints:

• Progressive sore throat
• Difficulty swallowing
• Low-grade fever
• Fatigue and loss of appetite

History of Present Illness:

Mia's symptoms began with mild rhinorrhea and sore throat 5 days ago. Over the past 48 hours, she developed difficulty swallowing, refused to eat, and became increasingly lethargic. Her parents report a low-grade fever and noticed swelling in her neck.

Past Medical History:

• Generally healthy
• Incomplete vaccination records due to frequent travel

Physical Examination

Vital Signs:

• Temperature: 38.7°C (101.7°F)
• Heart rate: 118 bpm
• Respiratory rate: 28 breaths/min
• Blood pressure: 92/58 mmHg
• Oxygen saturation: 97% on room air

General Appearance:

Mia appears ill, lethargic, and has difficulty swallowing her own saliva.

HEENT:

• Bilateral tonsillar enlargement with a thick, grayish-white pseudomembrane extending to the uvula and soft palate
• Attempted removal of the membrane results in bleeding
• Bilateral cervical lymphadenopathy with marked neck swelling ("bull neck" appearance)
• Nose: Serosanguineous discharge noted

Cardiovascular:

• Tachycardia with regular rhythm
• No murmurs or gallops

Respiratory:

• Mild inspiratory stridor
• Clear lung fields bilaterally

Laboratory and Diagnostic Studies

• Complete Blood Count:
  • WBC: 18,500/μL with 75% neutrophils
  • Hemoglobin: 11.8 g/dL
  • Platelets: 195,000/μL
• C-reactive protein: 95 mg/L
• Electrolytes: Within normal limits
• Renal function: Normal
• Liver function tests: Mild elevation of transaminases
• Throat swab: Gram stain shows gram-positive bacilli; culture pending
• ECG: Sinus tachycardia, no ST-T wave changes
• Chest X-ray: No significant findings

Clinical Course

Based on the clinical presentation and characteristic pseudomembrane, a presumptive diagnosis of respiratory diphtheria is made. The following actions are taken:

1. Mia is immediately placed in respiratory isolation.
2. Blood cultures are obtained before initiating antibiotics.
3. Diphtheria antitoxin (DAT) is urgently requested from the national stockpile.
4. Intravenous Penicillin G is started at 100,000 units/kg/day in four divided doses.
5. The local health department is notified for contact tracing and prophylaxis.
6. Mia is admitted to the pediatric intensive care unit for close monitoring.

Over the next 48 hours, Mia's condition stabilizes. The throat culture confirms toxigenic Corynebacterium diphtheriae. She completes a 14-day course of antibiotics and receives cardiac monitoring for potential myocarditis. After two weeks, she is discharged with follow-up appointments for cardiac and neurological evaluations to monitor for late complications.

2. Clinical Presentations of Diphtheria in Children

1. Classic Respiratory (Tonsillar-Pharyngeal) Diphtheria

   • Incubation period: 2-5 days (range: 1-10 days)
   • Initial symptoms: Low-grade fever, malaise, sore throat
   • Progression:
     • Development of thick, grayish-white pseudomembrane on tonsils, pharynx, or larynx
     • Membrane strongly adherent; bleeds when removal is attempted
     • Progressive difficulty swallowing and breathing
   • Cervical lymphadenopathy leading to "bull neck" appearance
   • Potential for airway obstruction in severe cases
   • Systemic toxicity: Pallor, tachycardia, prostration

2. Nasal Diphtheria

   • Often milder than pharyngeal form
   • Initial presentation: Serosanguineous or mucopurulent nasal discharge
   • Pseudomembrane formation in nasal passages
   • Excoriation of nares and upper lip due to discharge
   • May progress to pharyngeal involvement
   • Potential for chronic carriage state

3. Laryngeal Diphtheria

   • Can occur primarily or as an extension of pharyngeal disease
   • Symptoms:
     • Hoarseness progressing to aphonia
     • Barking cough (croup-like)
     • Inspiratory stridor
     • Respiratory distress and cyanosis in severe cases
   • High risk of airway obstruction requiring intubation or tracheostomy
   • Potential for sudden complete airway obstruction due to sloughing of membrane

4. Cutaneous Diphtheria

   • More common in tropical regions and areas with poor hygiene
   • Initial presentation: Non-healing ulcer or eczematous lesion
   • Characteristics:
     • Painless, often chronic ulcers
     • Gray membrane over the wound
     • Surrounding erythema and edema
   • Can serve as a reservoir for respiratory infection
   • Generally less toxic than respiratory forms but more contagious
   • May coexist with other skin pathogens (e.g., Staphylococcus aureus, Streptococcus pyogenes)

5. Malignant (Severe) Diphtheria

   • Rapid onset and progression of symptoms
   • Extensive pseudomembrane formation extending beyond tonsils
   • Marked neck edema and lymphadenopathy
   • Severe toxemia with high fever (>40°C or 104°F)
   • Complications:
     • Myocarditis with circulatory collapse
     • Acute renal failure
     • Pneumonia or respiratory failure
     • Disseminated intravascular coagulation (DIC)
   • High mortality rate even with appropriate treatment

6. Asymptomatic Carrier State

   • No clinical symptoms of disease
   • Positive throat or nasal culture for toxigenic C. diphtheriae
   • Can transmit the disease to susceptible individuals
   • More common in areas with inadequate immunization coverage
   • May persist for weeks to months without treatment

7. Diphtheria with Systemic Complications

   • Myocarditis:
     • Occurs in up to 20-30% of cases
     • Typically presents in the second week of illness
     • Manifestations: Tachycardia, arrhythmias, heart failure
     • ECG changes: ST-T wave abnormalities, heart block
   • Neuritis:
     • Usually occurs 1-3 months after onset of infection
     • Manifestations:
       • Bulbar palsy (difficulty swallowing, nasal regurgitation)
       • Ocular palsies (blurred vision, accommodation difficulties)
       • Limb weakness (usually symmetrical and ascending)
     • Generally reversible but may take weeks to months for complete recovery
   • Renal Complications:
     • Proteinuria and oliguria in severe cases
     • Acute tubular necrosis may occur

8. Neonatal Diphtheria

   • Rare in countries with good maternal immunization coverage
   • Presents within the first week of life
   • Manifestations:
     • Difficulty feeding
     • Feeble cry
     • Pseudomembrane formation (may be subtle)
   • Rapid progression to systemic disease
   • High mortality rate without prompt treatment

3. Viva Questions and Answers Related to Diphtheria in Children

1. Q: What is the causative agent of diphtheria, and how does it cause disease?

   A: Diphtheria is primarily caused by toxigenic strains of Corynebacterium diphtheriae, a gram-positive, non-spore-forming bacillus. Less commonly, it can be caused by toxigenic strains of C. ulcerans or C. pseudotuberculosis. The bacterium produces an exotoxin encoded by the tox gene, which is carried by a lysogenic beta-phage. This toxin is responsible for the local and systemic manifestations of the disease. The toxin inhibits protein synthesis in host cells by ADP-ribosylation of elongation factor 2 (EF-2), leading to cell death and tissue damage, particularly affecting the heart, nervous system, and kidneys.

2. Q: Describe the epidemiology of diphtheria globally and factors contributing to its persistence.

   A: Diphtheria was a major cause of childhood mortality worldwide before the introduction of widespread immunization. Currently, it remains endemic in many developing countries, with occasional outbreaks in areas with low vaccination coverage. Factors contributing to its persistence include:

   • Inadequate immunization coverage in some populations
   • Waning immunity in adults who don't receive booster doses
   • Population movements and displacement due to conflicts or natural disasters
   • The existence of asymptomatic carriers
   • Emergence of non-toxigenic strains that can become toxigenic through phage conversion
   Sporadic cases in developed countries often involve unvaccinated individuals or those with travel history to endemic areas.

3. Q: What is the composition of the diphtheria toxin, and how does it enter host cells?

   A: The diphtheria toxin is a single polypeptide of 535 amino acids, consisting of two functional domains:

   • Fragment A (N-terminal): Contains the catalytic domain responsible for the ADP-ribosylation of EF-2
   • Fragment B (C-terminal): Responsible for binding to the cell surface and facilitating entry of Fragment A into the cytoplasm
   The toxin enters host cells through receptor-mediated endocytosis. It binds to the heparin-binding epidermal growth factor-like growth factor (HB-EGF) receptor. After internalization, the acidic environment of the endosome causes a conformational change, allowing Fragment A to translocate into the cytoplasm where it exerts its toxic effect.

4. Q: How does the diphtheria pseudomembrane form, and what is its histological composition?

   A: The pseudomembrane formation is a hallmark of respiratory diphtheria. It forms due to the following process:

   1. Local tissue necrosis caused by the toxin
   2. Inflammatory response with exudation of fibrin
   3. Accumulation of dead tissue, leukocytes, and bacteria
   Histologically, the pseudomembrane consists of:
   • A superficial layer of necrotic epithelial cells
   • Fibrin network
   • Neutrophils, lymphocytes, and macrophages
   • Erythrocytes
   • Colonies of C. diphtheriae
   The membrane is strongly adherent to the underlying tissue due to fibrin attachment to the exposed vascular basement membrane. Attempted removal can cause bleeding due to this strong adherence.

5. Q: What are the key differences in clinical presentation between vaccinated and unvaccinated individuals with diphtheria?

   A: The clinical presentation can differ significantly between vaccinated and unvaccinated individuals:

   • Unvaccinated individuals:
     • More likely to develop classic, severe disease
     • Higher likelihood of extensive pseudomembrane formation
     • Greater risk of systemic complications (e.g., myocarditis, neuritis)
     • Higher mortality rate
   • Vaccinated individuals:
     • Generally milder disease course
     • May present as simple pharyngitis without pseudomembrane formation
     • Less likely to develop systemic toxicity
     • Reduced risk of complications
     • Lower mortality rate
   It's important to note that even in vaccinated individuals, waning immunity over time can lead to more severe presentations, emphasizing the importance of booster doses.

6. Q: Describe the current recommendations for diphtheria immunization in children and adults.

   A: While specific schedules may vary by country, the general recommendations are:

   • Primary series for children:
     • DTaP (Diphtheria, Tetanus, acellular Pertussis) at 2, 4, 6 months
     • Booster at 15-18 months
     • Second booster at 4-6 years
   • Adolescents:
     • Tdap (Tetanus, reduced diphtheria, acellular pertussis) at 11-12 years
   • Adults:
     • Td (Tetanus, reduced diphtheria) booster every 10 years
     • One dose of Tdap to replace one Td booster
   • Pregnant women:
     • Tdap with each pregnancy, preferably between 27-36 weeks gestation
   The 'reduced' diphtheria component in Td and Tdap contains less diphtheria toxoid than the pediatric DTaP formulation to minimize side effects in adults.

7. Q: What is the role of diphtheria antitoxin (DAT) in treatment, and what are the considerations for its administration?

   A: Diphtheria antitoxin (DAT) plays a crucial role in the treatment of diphtheria:

   • Function: Neutralizes circulating, unbound diphtheria toxin
   • Timing: Should be administered as early as possible, ideally within 48 hours of symptom onset
   • Dosage: Based on the site and severity of infection (20,000-100,000 units)
   • Administration: Intravenous infusion after sensitivity testing
   Considerations:
   • Does not neutralize toxin already bound to tissues
   • Risk of hypersensitivity reactions (equine serum)
   • Skin testing and desensitization may be necessary
   • Limited availability; often requires special release from national stockpiles
   • Should not delay administration for laboratory confirmation in suspected cases
   The use of DAT has significantly reduced mortality in diphtheria cases, making it a critical component of treatment.

8. Q: What antibiotic regimens are recommended for the treatment of diphtheria, and how do they differ for carriers?

   A: Antibiotic treatment serves to eradicate the organism, prevent toxin production, and reduce transmission. Recommended regimens include:

   • For confirmed cases:
     • Penicillin G: 100,000-150,000 units/kg/day IV in 4 divided doses for 14 days, or
     • Erythromycin: 40-50 mg/kg/day (max 2 g/day) IV or orally in 4 divided doses for 14 days
   • For carriers:
     • Erythromycin: 500 mg orally 4 times daily for 7-10 days, or
     • Penicillin V: 250 mg orally 4 times daily for 7-10 days
   Differences for carriers:
   • Shorter duration of treatment (7-10 days vs. 14 days for cases)
   • Preference for oral administration
   • Lower doses may be used
   Antibiotic susceptibility testing should be performed, and treatment adjusted if resistance is detected. Elimination of the organism should be confirmed with follow-up cultures.

9. Q: Describe the cardiac complications of diphtheria, their pathophysiology, and management.

   A: Cardiac complications, particularly myocarditis, are a major cause of mortality in diphtheria. Pathophysiology:

   • Direct toxic effect of diphtheria toxin on cardiomyocytes
   • Toxin-induced inhibition of protein synthesis in cardiac cells
   • Autonomic dysfunction affecting cardiac conduction
   Clinical features:
   • Usually occurs in the second week of illness
   • Ranges from mild ECG changes to severe congestive heart failure
   • Arrhythmias: Sinus tachycardia, atrial fibrillation, ventricular tachycardia
   • Conduction disturbances: First to third-degree heart block
   Management:
   • Close cardiac monitoring for at least 6 weeks
   • Serial ECGs and echocardiography
   • Bed rest and activity restriction
   • Management of arrhythmias and heart failure as per standard protocols
   • Temporary pacing may be required for severe conduction disturbances
   • Corticosteroids are controversial and not routinely recommended
   Prognosis: Mortality is high in severe cases, but many patients recover completely with appropriate management.

10. Q: What neurological complications can occur in diphtheria, and what is their typical time course?

    A: Neurological complications in diphtheria are typically due to the effects of the toxin on peripheral nerves and, less commonly, the central nervous system. Types and time course:

    • Early onset (1-2 weeks):
      • Palatal paralysis
      • Ciliary paralysis causing blurred vision and accommodation difficulties
    • Intermediate onset (4-6 weeks):
      • Cranial neuropathies (e.g., facial, glossopharyngeal, vagus nerves)
      • Proximal limb weakness
    • Late onset (8-12 weeks):
      • Distal peripheral neuropathy
      • Respiratory muscle weakness (rare but severe)
    Characteristics:
    • Usually symmetrical and motor-predominant
    • Sensory involvement is typically mild
    • Generally reversible, but recovery may take weeks to months
    • Resembles Guillain-Barré syndrome in some cases
    Management includes supportive care, physical therapy, and close monitoring for respiratory compromise. Most patients recover completely, though the process can be prolonged.

11. Q: How should close contacts of a diphtheria case be managed, and what defines a close contact?

    A: Management of close contacts is crucial for preventing the spread of diphtheria. Definition of close contacts:

    • Household members
    • Individuals with direct exposure to oral or respiratory secretions
    • Healthcare workers exposed without proper PPE
    • Classroom contacts in school settings
    Management protocol:
    1. Surveillance: Monitor for symptoms for 7 days from last exposure
    2. Throat and nasal swabs: Obtain cultures before antibiotic prophylaxis
    3. Antibiotic prophylaxis:
       • Erythromycin 500 mg orally 4 times daily for 7 days, or
       • Penicillin V 250 mg orally 4 times daily for 7 days
    4. Immunization status:
       • Review and update as necessary
       • Unimmunized contacts should receive a dose of diphtheria toxoid-containing vaccine
    5. Exclusion: Exclude from school/work until negative cultures and completion of antibiotics
    6. Follow-up cultures: Obtain at least 2 weeks after completing antibiotics
    Special considerations:
    • Immunocompromised individuals may require longer courses of antibiotics
    • Pregnant women should be closely monitored and receive erythromycin prophylaxis
    Effective contact management is essential for outbreak control and prevention of secondary cases.

12. Q: What are the indications for tracheostomy in diphtheria, and how should airway management be approached?

    A: Airway management is critical in diphtheria, particularly in laryngeal involvement. Indications for tracheostomy:

    • Severe upper airway obstruction not responding to medical management
    • Extensive pseudomembrane formation in the larynx or trachea
    • Impending respiratory failure despite other interventions
    • Need for prolonged mechanical ventilation
    Approach to airway management:
    1. Assessment:
       • Monitor for stridor, retractions, cyanosis
       • Evaluate oxygen saturation and blood gases
       • Assess extent of pseudomembrane with laryngoscopy if possible
    2. Initial management:
       • Humidified oxygen
       • Positioning (upright or semi-recumbent)
       • Avoid agitation or unnecessary manipulation of the airway
    3. Intubation considerations:
       • High risk of dislodging the pseudomembrane
       • Potential for complete airway obstruction during the procedure
       • Should be performed by the most experienced operator available
    4. Tracheostomy:
       • May be preferred over intubation in some cases
       • Allows for better management of secretions and pseudomembrane
       • Surgical team should be prepared for possible extension of the incision if the pseudomembrane extends into the trachea
    Post-procedure care:
    • Close monitoring in an intensive care setting
    • Regular suctioning and respiratory physiotherapy
    • Continued antibiotic therapy and antitoxin administration
    The decision for tracheostomy should be made early if indicated, as delayed intervention can lead to increased morbidity and mortality.