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