Corynebacterium diphtheriae

Background

History

• The name diphtheria is derived from the Greek word for leather, based on the appearance of the pseudomembrane that the organism produces

Microbiology

• Non-spore-forming, pleomorphic, unencapsulated, nonmotile Gram-positive bacillus with clubbed ends
• Needs to be cultured on special media, so notify the lab
  • On Loeffler medium, outgrows other throat flora by 12 to 18 hours
• Classic "Chinese character" appearance on Gram stain (pallisading) of all corynebacteria
• Metachromatic granules on methylene blue
• Four biovars: gravis, intermedius, mitis, and belfanti
  • Based on morphology, fermentation, and hemolysis, but now more often based on PCR ribotyping
  • Not clinically significant
• Exotoxin production is provided by the tox gene
  • The gene is carried by bacteriophages, which convert non-toxigenic strains into toxigenic ones
  • Toxin production is not necessary for the life cycle

Pathophysiology

• Toxigenic strains produce a polypeptide exotoxin that is cleaved into two segments, which comprise three domains
  • Segment B contains the receptor-binding and transmembrane domains, and facilitates binding to heparin-binding epidermal growth factor receptor
  • Segment A is the active segment, which enters the cytosol after B binds and inactivates mammalian tRNA translocase (elongation factor 2), thus stopping protein synthesis and killing the cell
    • A single molecule is enough to kill a cell
• The exotoxin affects all cells, but heart, nerves, and kidneys are particularly sensitive
• In the respiratory tract, exotoxin causes the formation of a necrotic coagulum of fibrin, WBCs, RBCs, and epithelial cells
  • Appears clinically as a pseudomembrane
• The lethal dose may be as low as 100 ng/kg body weight

Epidemiology

• Spread by droplets and direct contact, and via fomites
• Mostly occurs in colder months
• Asymptomatic carriage is an important reservoir for the organism, with 3-5% carriage rates in endemic areas
  • May also be carried by horses, cattle, and domestic cats
• Disease is rare in immunized populations
• Risk factors include travel or residence within an epidemic or endemic setting, and a history of inadequate vaccination
  • Currently, the highest rates are seen in India, and particularly in Kerala state in people older than 10 years
• Maternal antibodies provide immunity until about 6 months

Clinical Manifestations

Diphtheria

• Clinical syndrome of pharyngeal infection with systemic toxicity caused by C. diphtheriae and C. ulcerans
• Incubation period of 2 to 4 days
• Low-grade fever, hoarseness, pain, and laryngeal pseudomembrane that can cause stridor and obstruction
  • Pseudomembrane starts white but later dirty gray with patches of green or black
  • Bleeding if membrane is removed
  • Can have a bullneck appearance
• Can also have serosanguineous nasal discharge and cervical lymphadenopathy
• Palatal paralysis and cranial nerve defects may cause dysphagia
• Systemic symptoms related to extent of local disease

Myocarditis

• Occurs in 10-25% of cases
• Can range from acute heart failure and cardiogenic shock to more subacute heart failure and dilatation
  • Can be monitored with AST (?and troponin?)
• ECG may show ST-T wave changes and first-degree heart block, which can progress to complete heart block
  • Mortality is higher with ECG changes, and highest with AV blocks and LBBB
  • Can be permanent
  • Monitor for arrhythmias

Neurotoxicity

• Acutely, can manifest as paralysis of the soft palate and posterior pharynx, causing dysphagia
  • Followed by cranial nerve defects
• After 10 days to 3 months, can develop a peripheral motor neuropathy from demyelination
  • Typically descending paralysis by can still be confused with Guillain-Barré syndrome
  • Generally fully resolves with time

Acute Tubular Necrosis

• Caused by both the toxin itself and the septic shock

Complications and Prognosis

• Suffocation from aspiration of the pseudomembrane
• Rarely, bacteremia, endocarditis, and arthritis from hematogenous spread
• Can have post-infectious, autoimmune-mediated complications including neuropathy and carditis
• Mortality 3-12% even now, usually from asphyxiation or myocarditis, but is rare in immunized patients

Cutaneous Diphtheria

• Usually caused by non-toxigenic strains
• Can also cause chronic non-healing ulcers with dirty-gray membrane (or not), often with concomitant Staphylococcus aureus or Streptococcus pyogenes
• Generally not invasive and can cause immunity, but also contributes to the organism's reservoir

Asymptomatic Carrier State

• C. diphtheriae not particularly invascive and can colonize the respiratory tract and skin
• Common in areas that do not vaccinate, as well as inner cities and rural areas

Non-Toxigenic Strains

• As well as cutaneous diphtheria, these strains can also cause bacteremia and endocarditis, particularly in those with chronic alcohol use, dental disease, and intravenous drug use

Differential Diagnosis

• Infectious mononucleosis
• Streptococcal or viral pharyngitis
• Vincent angina
• Acute epiglottitis
• Retropharyngeal space infection
• Oropharyngeal candidiasis
• Acute HIV syndrome

Diagnosis

• Clinical diagnosis based on:
  • Mildly painful tonsilitis or pharyngitis with a membrane, especially if the memrane extends to the uvula and soft palate
  • Adenopathy and cervical swelling, especially if assocaited with memranous pharyngitis and signs of systemic toxicity
  • Hoarseness and stridor
  • Palatal paralysis
  • Serosanguineous nasal discharge with associated mucosal membrane
  • Temperature not over 102.5ºF (39ºC)
  • History of travel to endemic country
• Collected specimens from nose or throat, and any mucosal or cutaneous lesions
  • Ideally collected from below the pseudomembrane
  • Can also collect a piece of pseudomembrane
  • Notify lab, who will use modified Tinsdale agar or cystine-tellurite blood agar
  • Gram stain should show classic coryneform "Chinese letter" appearance, which may be dismissed as normal respiratory flora unless specific testing for diphtheria is requested
• Culture requires Tinsdale medium (contains teluride and cysteine), inhibits non-pathogenic Corynebacterium
• PCR for the toxin gene exists, and is followed by serology to demonstrate toxin production
• Serology is done for tox gene positive strains using the Elek test

Management

Pharyngeal Diphtheria

• Supportive management, with a focus on airway protection
  • Preemptive intubation is recommended in most situations
  • May require tracheotomy if severe
  • May be useful to add carnithine to improve myocardial function
• If concern for pharyngeal diphtheria, then need to treat presumptively with antitoxin and penicillin while awaiting confirmation of the diagnosis
• Start with with equine-derived diphtheria antitoxin (DAT)
  • Prevents toxin from entering the cell
  • First must rule out horse protein hypersensitivity
    • History of allergy
    • Scratch test: drop of 1:1000 dilution applied to superficial scratch; if no wheal in 15 minutes, inject 0.02 mL of 1:1000 dilution intracutaneously
      • Epipen at the ready!
  • Dose depends on duration of symptoms
    • ≤48 hours: 20,000-40,000 units
    • ≥3 days: 80,000-120,000 units, including anyone with neck swelling
    • Nasopharyngeal: 40,000-80,000 units
  • Diluted in 250-500 mL NS and infused over 60-120 minutes
  • 10% risk of serum sickness
• Also treat with a 14-day course of an appropriate antibiotic
  • Procaine penicillin G 600,000 units IM q12h (300,000 units if weight ≤10 kg)
    • Can switch or oral penicillin once able to take oral medication
  • Erythromycin 40 mg/kg/day (max 2 g) PO/IV divided qid
• Test of cure should be done at least 24 hours after completing treatment, with two cultures from both nose and throat at least 24 hours apart
  • If still positive, extend treatment for another 10 days
• After acute illness, still need to vaccinate since infection does not generate long-term immunity

Cutaneous Diphtheria

• Treated with a 14-day course of antibiotics, as above
• Test of cure should be done at least 24 hours after completing treatment, with two cultures from cutaneous lesions at least 24 hours apart

Asymptomatic Carrier State

• Should be treated to prevent transmission to others
• Benzathine penicillin G 600,000 units (<6 years) to 1,200,000 units (≥6 years) IM once, or erythromycin 40 mg/kg/day (max 1 g) for 7 to 10 days
• If cultures still positive after treatment, do another 10-day course of erythromycin (more effective than penicillin)

Prevention

Infection Control

• Contact precautions for cutaneous diphtheria, contact and droplet precautions for pharyngeal diphtheria
• Must be in isolation until treatment is completed and until two negative cultures collected at least 24 hours apart

Prophylaxis

• Indicated for healthcare workers exposed to nasopharyngeal secretions, household contacts, other habitual close contacts, people sharing utensils or kitchen facilities, and childcare workers
  • Indicated regardless of immunization status
  • Even if the contact is transient, but excludes those who were wearing appropriate PPE at the time
• Procedure
  • Monitor for symptoms for 7 days
  • Collect culture specimens before treatment
  • Antimicrobial prophylaxis with either benzathine penicillin G 600,000 units (<30 kg) to 1,200,000 units (≥30 kg) IM once, or erythromycin 40 mg/kg/day (max 1 g) for 7 to 10 days
  • Repeat culture after treatment, and repeat a 10-day course of erythromycin if still positive (more effective than penicillin)
• If previously vaccinated, give a Td/Tdap booster if it's been more than 5 years from last dose
• If not fully vaccinated, complete the vaccine series

Vaccination

• The available vaccine is against diphtheria toxin, so protects against the harmful effects of infection but does not directly prevent infection
  • Asymptomatic carriage still occurs, though at a lower population level
• Diphtheria toxoid vaccine is given as a ≥3-dose series in childhood
  • Typically in combination with others (e.g. DTaP-IPV-HiB at 2, 4, 6, and 18 months)
  • Adult catch-up schedule would be Tdap followed 4 weeks later by Td followed 6 to 12 months later by another Td
• Adults should get a Tdap booster in adulthood at least once, and Td booster every 10 years