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Internal Medicine

Diphtheria

An acute bacterial toxigenic infectious disease caused by gram-positive bacillus, Corynebacterium diphtheriae.


Epidemiology

  • Source: Secretions and discharges (infected person or carriers)
  • Transmission: Droplet, secretions, direct contact
    • Infection is spread solely among humans
  • Portal of entry: Respiratory tract
  • Incubation period: 2-5 days
Trend of diphtheria cases reported globally and from India, 1989–2015
Trend of diphtheria cases reported globally and from India, 1989–2015 | Murhekar, M. (2017). Epidemiology of Diphtheria in India, 1996-2016: Implications for Prevention and Control. The American Journal of Tropical Medicine and Hygiene, 97(2), 313–318. https://doi.org/10.4269/ajtmh.17-0047

Microbiology

Corynebacterium diphtheriae

Nonmotile, noncapsulated, club-shaped, Gram-positive bacillus
  • Pathogenicity due to:
    • Ability to colonise nasopharyngeal cavity and/or skin
    • Diphtheria toxin
Electron micrograph of corynebacteriophage ß, which carries tox
Electron micrograph of corynebacteriophage ß, which carries tox. Following lysogenic conversion with corynebacteriophage ß, or closely related corynebacteriophages, nontoxigenic strains of C diphtheriae become toxigenic. | Murphy JR. Corynebacterium Diphtheriae. In: Baron S, editor. Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996. Chapter 32. Available from: https://www.ncbi.nlm.nih.gov/books/NBK7971/

Macleod classification:

McLeod and Anderson classified diphtheria bacilli, based on the colony characteristics on Tellurite medium and other properties like biochemical reactions and severity of disease.
C. diphtheriae biotypeColony appearanceHemolysisGlycogen & starch fermentation
GravisDaisy headVariableFermenting
IntermediusFrog eggNon-hemolyticNon-fermenting
MitisPoached eggHemolytic Non-fermenting

Pathophysiology

Pathogenesis of diphtheria
Pathogenesis of diphtheria | Murphy JR. Corynebacterium Diphtheriae. In: Baron S, editor. Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996. Chapter 32. Available from: https://www.ncbi.nlm.nih.gov/books/NBK7971/?report=classic

Enter respiratory tract

Proliferate and liberate powerful exotoxin
(Principal cause of systemic and local lesions)

Necrosis of the epithelial cells
+
Liberation of serous and fibrinous material

Forms a thick, gray-green fibrin membrane
Pseudomembrane
(composed of fibrin, bacteria, and inflammatory cells)

  • Surrounding tissue: Inflamed and edematous
  • Organs principally affected: Heart, kidney and myocardium

Presentation

Acute onset

  • Fever, malaise and headache
  • Toxic look

Clinical types (depends on the site of involvement):

  • Respiratory diphtheria (M/C):
    • Faucial/tonsillopharyngeal diphtheria
    • Nasopharyngeal diphtheria
    • Laryngotracheal diphtheria
  • Cutaneous diphtheria

Faucial/tonsillopharyngeal diphtheria:

M/C respiratory diphtheria
  • Redness and swelling over the fauces
  • Pseudomembrane
    • The exudates coalesce to form a greyish white pseudomembrane, which extends to surrounding areas.
    • Localised on posterior pharynx or tonsil
    • Wipes off easily, resulting in bleeding
    • Extends to become thick blue-white to grey-black and adherent
  • Bull neck diphtheria (severe cases, involvement of cervical lymph nodes)
  • Sore throat, dysphagia and muffled voice

Nasal diphtheria (mildest respiratory diphtheria):

  • Unilateral/bilateral serosanguinous discharge from the nose (localised to septum/turbinates)
  • Excoriation of upper lip

Laryngotracheal diphtheria:

  • Preceded by Pharyngotonsillar Disease
  • Membrane over the larynx leads toBrassy cough, stridor, respiratory distress

Cutaneous diphtheria:

  • Diphtheritic lesions in skin and conjunctiva
    • Secondary to previous skin lesion or infections
  • Ulcer:
    • Surrounded by erythema
    • Covered by membrane
A diphtheria skin lesion on the leg. Corynebacterium diphtheriae can not only affect the respiratory system, but the skin as well, where it manifests as an open wound.
A diphtheria skin lesion on the leg. Corynebacterium diphtheriae can not only affect the respiratory system, but the skin as well, where it manifests as an open wound. | CDC – Public Health Image Library, ID#:1941 Public Domain, https://commons.wikimedia.org/w/index.php?curid=717943

Complications

Respiratory failure (M/C)

  • Due to occlusion of the airways by the membrane & loss of motor function (due to action of diphtheria toxin on peripheral motor neurons)

Myocarditis

  • By 2nd week of illness
  • Can lead to: Congestive cardiac failure, arrhythmias → Sudden death

Diphtheric mono/polyneuropathy (loss of motor function due to action of diphtheria toxin on peripheral motor neurons):

  • Palatal palsy (by 2nd week of illness)
    • Clinically manifested as: Nasal twang & nasal regurgitation
  • Ocular palsy (by 3rd week of illness)
  • Loss of accommodation (visual blurring, inability to read)
  • Generalized polyneuritis (by 3rd-6th weeks of illness)
A case of diphtheria complicated with myocarditis and polyneuropathy
A case of diphtheria complicated with myocarditis and polyneuropathy | Murhekar, M. (2017). Epidemiology of Diphtheria in India, 1996-2016: Implications for Prevention and Control. The American Journal of Tropical Medicine and Hygiene, 97(2), 313–318. https://doi.org/10.4269/ajtmh.17-0047

Renal complications:

  • Oliguria
  • Proteinuria

Diagnosis

High index of suspicion

  • SGOT ↑
  • CPK-MB ↑
  • Troponin T (kit test)
  • Urea, creatinine ↑

Rapid diagnosis:

  • Culture: Albert stain
    • Swab from the oropharynx and larynx
  • Primary isolation media: Loeffler agar, Mueller-Miller tellurite agar,
    or Tinsdale tellurite agar
Corynebacterium diptheriae in Albert Stain
Corynebacterium diptheriae in Albert Stain

Elek immunodiffusion test (M/C in vitro assay for toxigenicity):

  • Based on the double diffusion of diphtheria toxin and antitoxin in an agar medium
  • Procedure:
    • Sterile, antitoxin-saturated filter paper strip is embedded in the culture medium, and C diphtheriae isolates are streak-inoculated at a 90° angle to the filter paper.
    • Production of diphtheria toxin can be detected within 18-48 hours by the formation of a toxin-antitoxin precipitin band in the agar.
Elek immunodiffusion test: Sterile filter paper impregnated with diphtheria antitoxin is imbedded in agar culture medium. Isolates of C diphtheriae are then streaked across the plate at an angle of 90° to the antitoxin strip. Toxigenic C diphtheriae is detected because secreted toxin diffuses from the area of growth and reacts with antitoxin to form lines of precipitin.
Elek immunodiffusion test: Sterile filter paper impregnated with diphtheria antitoxin is imbedded in agar culture medium. Isolates of C diphtheriae are then streaked across the plate at an angle of 90° to the antitoxin strip. Toxigenic C diphtheriae is detected because secreted toxin diffuses from the area of growth and reacts with antitoxin to form lines of precipitin. | Murphy JR. Corynebacterium Diphtheriae. In: Baron S, editor. Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996. Chapter 32. Available from: https://www.ncbi.nlm.nih.gov/books/NBK7971/?report=classic

ECG (for cardiac complications):

  • Findings:
    • T-wave inversion
    • Sinus tachycardia
    • 2° AV block

Differential diagnosis:

  • Acute streptococcal membranous tonsillitis
    • High fever but are less toxic and the membrane is confined to the tonsils
  • Viral (adenovirus) membranous tonsillitis
    • High fever, sore throat, membranous tonsillitis with normal leukocyte count
    • Self limited course of 4-8 days
  • Herpetic tonsillitis
  • Aphthous stomatitis
  • Thrush
  • Infectious mononucleosis
  • Agranulocytosis
  • Leukemia

Management

Goals of management:

  1. Early detection
  2. Isolation
  3. Treatment

Treatment for cases:

  1. Diphtheria antitoxin,  IM/IV
    • Dose: 20,000-100,000 units
    • Degree of protection offered by the diphtheria antitoxin is inversely proportional to the duration of clinical illness
    • Repeat doses may be given if clinical improvement is suboptimal.
  2. Penicillin or Erythromycin  (5-6 days)
    • Actions:
      1. Terminate toxin production
      2. Limit proliferation of bacteria
      3. Prevent spread of organism to contacts
      4. Prevent the development of carriers

Treatment for carriers:

  • Oral Erythromycin
    • 10-day course

Supportive therapy:

  • Bed rest
    • 2-3 weeks
  • Avoid sudden exertion
  • Monitored for:
    • Airway obstruction and managed
      • Tracheostomy (if required)
    • Changes in rate and rhythm of heart
  • Palatal palsy:
    • Nasogastric feeding.
  • Generalized weakness due to polyneuritis:
    • Treated as for poliomyelitis or Guillain-Barre syndrome

Prevention:

Treatment should be followed by active immunization as clinical disease does not confer active immunity.

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