Diphtheria

Dr. Neha Sharma

Introduction 

  • Diphtheria is an acute, communicable, toxin-mediated bacterial infection.

  • It primarily affects the upper respiratory tract, especially the tonsils, pharynx, and larynx.

  • The disease is caused by Corynebacterium diphtheriae.

  • A characteristic feature of diphtheria is the formation of a grayish-white pseudomembrane over the throat.

  • The pseudomembrane may lead to airway obstruction and respiratory distress.

  • Diphtheria toxin is responsible for both local tissue necrosis and systemic toxicity.

  • Systemic absorption of the toxin can cause serious complications such as myocarditis and neuropathy.

  • Humans are the only reservoir of infection.

  • The disease spreads mainly through respiratory droplets and close contact.

  • Diphtheria was a major cause of childhood mortality before the introduction of vaccination.

  • The incidence has markedly decreased due to routine immunization programs.

  • However, diphtheria still occurs in areas with low immunization coverage, overcrowding, and poor socioeconomic conditions.

  • Diphtheria is a vaccine-preventable disease, and immunization remains the cornerstone of prevention.

Causative Agent

Diphtheria is caused by Corynebacterium diphtheriae.

Morphological Characteristics

  • Gram-positive, pleomorphic bacilli

  • Club-shaped rods with irregular swelling at one end

  • Arranged in Chinese-letter or palisade pattern due to snapping division

  • Non-motile and non-spore forming

  • Aerobic or facultative anaerobic

Staining Features

  • Gram stain: Gram-positive pleomorphic bacilli

  • Albert stain: Green bacilli with bluish-black metachromatic (volutin) granules at the poles

Biotypes

Based on colony morphology and biochemical reactions:

  1. Gravis

  2. Mitis

  3. Intermedius

 Important: Disease severity depends on toxin production, not on biotype.

Virulence Factor: Diphtheria Toxin

The most important virulence factor of C. diphtheriae is the diphtheria exotoxin.

  • The toxin is encoded by the tox gene, which is carried by a β-corynephage

  • Only toxigenic strains produce classical diphtheria

Mechanism of Action

  • The toxin inhibits protein synthesis by inactivating elongation factor-2 (EF-2)

  • This leads to cell death and tissue necrosis

Effects of the Toxin

  • Local tissue damage → pseudomembrane formation

  • Systemic absorption → damage to:

    • Heart (myocarditis)

    • Nervous system (neuritis)

    • Kidneys (rare)

 

Epidemiology

  • Humans are the only reservoir

  • Occurs worldwide but more common in:

    • Unimmunized or partially immunized children

    • Overcrowded living conditions

    • Poor sanitation and nutrition

  • No natural immunity; protection is acquired only through vaccination or previous infection

  • Waning immunity in adults can lead to outbreaks if booster doses are not taken

 

Mode of Transmission

  • Respiratory droplets during coughing or sneezing

  • Direct contact with secretions from infected individuals

  • Rarely through contaminated fomites

The disease spreads easily in close-contact settings, such as households and schools.

Incubation Period

  • Usually 2–5 days

  • Range: 1–10 days

 

Pathogenesis

  1. C. diphtheriae enters the body through the respiratory tract

  2. The organism colonizes the tonsils, pharynx, or larynx

  3. Local multiplication occurs without tissue invasion

  4. The exotoxin causes:

    • Local epithelial cell death

    • Inflammation and exudation

  5. A pseudomembrane is formed, composed of:

    • Fibrin

    • Necrotic epithelial cells

    • Inflammatory cells

    • Bacteria

 Clinical importance:
Forceful removal of the pseudomembrane causes bleeding and may worsen airway obstruction.

  1. Absorbed toxin enters the bloodstream, leading to systemic complications

 

Clinical Manifestations

1. Respiratory Diphtheria (Most Common Form)

  • Sore throat

  • Low-grade fever

  • Malaise

  • Dysphagia (difficulty in swallowing)

  • Grayish-white pseudomembrane over tonsils or pharynx

  • Cervical lymphadenopathy leading to “bull neck” appearance

2. Laryngeal Diphtheria

  • Hoarseness of voice

  • Stridor

  • Severe respiratory distress

  • High risk of asphyxia, especially in children

3. Nasal Diphtheria

  • Serosanguinous nasal discharge

  • Mild systemic symptoms

  • Common in infants

4. Cutaneous Diphtheria

  • Chronic, non-healing skin ulcers

  • Usually mild but acts as a source of infection

 

Systemic Complications

Complications occur due to circulating diphtheria toxin:

1. Cardiac Complications

  • Myocarditis (most serious)

  • Arrhythmias

  • Heart failure

  • Occurs during the 2nd–3rd week of illness

2. Neurological Complications

  • Peripheral neuritis

  • Palatal paralysis (nasal speech, regurgitation of food)

  • Cranial nerve palsies

  • Limb weakness

3. Others

  • Renal damage (rare)

  • Secondary bacterial infections

 

Laboratory Diagnosis

1. Specimen Collection

Specimen of Choice

  • Throat swab from:

    • Edge of the pseudomembrane

    • Area beneath the pseudomembrane (if safely possible)

 Important:

  • Swabs should be collected before starting antibiotics or antitoxin

  • Forceful removal of pseudomembrane should be avoided as it may cause bleeding

Other Specimens

  • Nasal swab (in nasal diphtheria)

  • Swab from skin lesions (cutaneous diphtheria)

2. Microscopic Examination

Gram Staining

  • Shows:

    • Gram-positive, pleomorphic bacilli

    • Club-shaped rods

    • Arranged in Chinese-letter (V, L, Y) pattern

 Limitation:

  • Gram stain is suggestive but not confirmatory

Albert Staining (Special Stain)

  • Demonstrates metachromatic (volutin) granules

  • Findings:

    • Bacilli: Green

    • Granules: Bluish-black, present at the poles

 Exam Point:
Albert stain is highly useful for presumptive diagnosis.

3. Culture

Culture is essential for definitive identification of the organism.

Culture Media Used

a) Löffler’s Serum Slope

  • Enriched medium

  • Enhances:

    • Rapid growth (within 6–8 hours)

    • Formation of metachromatic granules

  • Useful for early diagnosis

b) Potassium Tellurite Agar (Selective Medium)

  • Inhibits growth of normal throat flora

  • Corynebacterium diphtheriae reduces tellurite to tellurium

Colony Appearance:

  • Gray to black colonies

  • Different biotypes show characteristic colony morphology

Incubation Conditions

  • Temperature: 35–37°C

  • Atmosphere: Aerobic

  • Time: 24–48 hours

4. Identification Tests

After culture, colonies are identified by:

  • Gram staining

  • Albert staining

  • Biochemical tests (sugar fermentation patterns)

  • Biotype differentiation (Gravis, Mitis, Intermedius)

5. Demonstration of Toxin Production (Most Important Step)

 Clinical significance:
Only toxigenic strains cause classical diphtheria. Hence, toxin demonstration is mandatory.

Elek’s Gel Precipitation Test (Gold Standard)

  • In vitro immunodiffusion test

  • Principle:

    • Diphtheria toxin diffuses from bacterial growth

    • Antitoxin diffuses from filter paper strip

    • Formation of precipitin lines indicates toxin production

 Interpretation:

  • Positive test → toxigenic strain

  • Negative test → non-toxigenic strain

Molecular Methods

  • PCR for tox gene

  • Rapid and highly sensitive

  • Used in reference or advanced laboratories

6. Serological Tests

  • Antibody detection has limited diagnostic value

  • Mainly useful for:

    • Epidemiological studies

    • Assessing immune status

  • Not recommended for routine diagnosis

Treatment

1. Diphtheria Antitoxin

  • Neutralizes circulating toxin

  • Must be administered as early as possible

  • Does not reverse already established tissue damage

2. Antibiotic Therapy

  • Penicillin or Erythromycin

  • Eliminates the organism and prevents transmission

3. Supportive Care

  • Airway management

  • Bed rest

  • Cardiac monitoring

  • Isolation of the patient

 

Prevention and Control

Immunization

  • Diphtheria toxoid vaccine given as:

    • DPT / DT in children

    • Td booster in adolescents and adults

  • Booster doses are essential due to waning immunity

Public Health Measures

  • Isolation of cases

  • Chemoprophylaxis for close contacts

  • Surveillance and outbreak control

Public Health Importance

  • Diphtheria is a vaccine-preventable disease

  • Resurgence occurs due to:

    • Inadequate vaccination

    • Migration

    • Vaccine hesitancy

  • Early diagnosis and rapid treatment significantly reduce mortality

 

MCQs

1. Diphtheria is caused by:

A. Streptococcus pyogenes
B. Corynebacterium diphtheriae
C. Bordetella pertussis
D. Staphylococcus aureus
Answer: B

2. Diphtheria is primarily a disease of:

A. Skin
B. Gastrointestinal tract
C. Upper respiratory tract
D. Central nervous system
Answer: C

3. The characteristic lesion of diphtheria is:

A. Ulcer
B. Vesicle
C. Pseudomembrane
D. Abscess
Answer: C

4. The pseudomembrane in diphtheria is composed mainly of:

A. Mucus only
B. Necrotic tissue and fibrin
C. Pus cells
D. Blood clot
Answer: B

5. Attempted removal of pseudomembrane causes:

A. Healing
B. No effect
C. Bleeding
D. Scar formation
Answer: C

6. Corynebacterium diphtheriae is:

A. Gram-negative cocci
B. Gram-positive bacillus
C. Acid-fast bacillus
D. Spirochete
Answer: B

7. Arrangement of C. diphtheriae is typically:

A. Chains
B. Clusters
C. Chinese-letter pattern
D. Diplococci
Answer: C

8. Special stain used to demonstrate metachromatic granules is:

A. Ziehl–Neelsen stain
B. Giemsa stain
C. Albert stain
D. India ink
Answer: C

9. Metachromatic granules contain:

A. Glycogen
B. Lipid
C. Polyphosphate
D. Protein
Answer: C

10. C. diphtheriae is:

A. Motile
B. Spore forming
C. Non-motile and non-spore forming
D. Flagellated
Answer: C

11. Virulence of diphtheria depends mainly on:

A. Capsule
B. Spore
C. Exotoxin production
D. Enzyme secretion
Answer: C

12. Diphtheria toxin inhibits:

A. DNA synthesis
B. RNA synthesis
C. Protein synthesis
D. Cell wall synthesis
Answer: C

13. Diphtheria toxin acts by inactivating:

A. RNA polymerase
B. Ribosome
C. Elongation factor-2 (EF-2)
D. DNA gyrase
Answer: C

14. The tox gene is carried by:

A. Plasmid
B. Transposon
C. β-corynephage
D. Chromosome only
Answer: C

15. Only which strains cause classical diphtheria?

A. Non-capsulated strains
B. Non-toxigenic strains
C. Toxigenic strains
D. Resistant strains
Answer: C

16. Common biotypes of C. diphtheriae include all EXCEPT:

A. Gravis
B. Mitis
C. Intermedius
D. Lenta
Answer: D

17. Humans are the:

A. Intermediate host
B. Accidental host
C. Only reservoir
D. Animal reservoir
Answer: C

18. Mode of transmission of diphtheria is mainly:

A. Feco-oral route
B. Vector-borne
C. Respiratory droplets
D. Blood transfusion
Answer: C

19. Incubation period of diphtheria is usually:

A. 1–2 hours
B. 2–5 days
C. 10–14 days
D. 1 month
Answer: B

20. The most common form of diphtheria is:

A. Nasal
B. Cutaneous
C. Respiratory
D. Intestinal
Answer: C

21. “Bull neck” appearance is due to:

A. Thyroid enlargement
B. Edema and lymphadenopathy
C. Muscle spasm
D. Fat deposition
Answer: B

22. Most serious complication of diphtheria is:

A. Pneumonia
B. Myocarditis
C. Hepatitis
D. Nephritis
Answer: B

23. Neurological complication commonly seen is:

A. Seizures
B. Peripheral neuritis
C. Meningitis
D. Stroke
Answer: B

24. Specimen of choice for diagnosis is:

A. Blood
B. Sputum
C. Throat swab
D. Urine
Answer: C

25. Best site for collecting throat swab is:

A. Center of pseudomembrane
B. Edge of pseudomembrane
C. Tongue
D. Cheek
Answer: B

26. Culture medium that enhances granule formation is:

A. Blood agar
B. Chocolate agar
C. Löffler’s serum slope
D. MacConkey agar
Answer: C

27. Selective medium for C. diphtheriae is:

A. TCBS agar
B. Lowenstein–Jensen medium
C. Potassium tellurite agar
D. CLED agar
Answer: C

28. Colonies on tellurite agar appear:

A. Green
B. Yellow
C. Black or gray
D. Red
Answer: C

29. Gold standard test for toxin detection is:

A. PCR
B. ELISA
C. Elek’s test
D. Agglutination
Answer: C

30. Elek’s test is based on:

A. Agglutination
B. Complement fixation
C. Gel precipitation
D. Hemagglutination
Answer: C

31. Treatment of diphtheria includes all EXCEPT:

A. Antibiotics
B. Antitoxin
C. Vaccination only
D. Supportive care
Answer: C

32. Drug of choice for diphtheria treatment is:

A. Penicillin or erythromycin
B. Ciprofloxacin
C. Tetracycline
D. Vancomycin
Answer: A

33. Diphtheria antitoxin acts by:

A. Killing bacteria
B. Neutralizing circulating toxin
C. Preventing colonization
D. Stimulating immunity
Answer: B

34. Antitoxin is most effective when given:

A. Late in disease
B. After complications
C. Early in disease
D. Only after culture confirmation
Answer: C

35. Diphtheria vaccine is a:

A. Live attenuated vaccine
B. Killed vaccine
C. Toxoid
D. Subunit vaccine
Answer: C

36. Diphtheria toxoid is given as part of:

A. BCG
B. OPV
C. DPT
D. Hepatitis B vaccine
Answer: C

37. Booster doses are required because:

A. Vaccine is weak
B. Natural immunity is strong
C. Immunity wanes with time
D. Bacteria mutate rapidly
Answer: C

38. Cutaneous diphtheria presents as:

A. Vesicles
B. Bullae
C. Chronic non-healing ulcers
D. Papules
Answer: C

39. Nasal diphtheria commonly occurs in:

A. Adults
B. Elderly
C. Infants
D. Pregnant women
Answer: C

40. Systemic toxicity in diphtheria is due to:

A. Bacterial invasion
B. Capsule
C. Circulating toxin
D. Immune complex deposition
Answer: C

41. Removal of pseudomembrane is discouraged because it may cause:

A. Healing
B. Bleeding and toxin absorption
C. Pain only
D. Scar formation
Answer: B

42. C. diphtheriae grows best in:

A. Anaerobic conditions
B. Aerobic conditions
C. Microaerophilic conditions
D. CO₂-free environment
Answer: B

43. Which is NOT a complication of diphtheria?

A. Myocarditis
B. Neuritis
C. Acute renal failure
D. Bronchial asthma
Answer: D

44. Case fatality rate is highest in:

A. Immunized adults
B. Unimmunized children
C. Vaccinated adolescents
D. Carriers
Answer: B

45. Isolation of diphtheria patient is important to:

A. Reduce pain
B. Prevent toxin action
C. Prevent transmission
D. Increase immunity
Answer: C

46. Chemoprophylaxis is recommended for:

A. General population
B. Hospital staff only
C. Close contacts
D. Recovered patients
Answer: C

47. Diphtheria is best prevented by:

A. Early antibiotics
B. Good nutrition
C. Immunization
D. Isolation alone
Answer: C

48. Which organ is most commonly affected by diphtheria toxin?

A. Liver
B. Heart
C. Lung
D. Spleen
Answer: B

49. Palatal paralysis is due to:

A. Muscle damage
B. Bone involvement
C. Peripheral neuritis
D. Edema
Answer: C

50. Diphtheria is a:

A. Viral disease
B. Protozoal disease
C. Toxin-mediated bacterial disease
D. Fungal infection
Answer: C