Corynebacterium diphtheriae: Difference between revisions
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Corynebacterium diphtheriae
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*Can range from acute heart failure and cardiogenic shock to more subacute heart failure and dilatation |
*Can range from acute heart failure and cardiogenic shock to more subacute heart failure and dilatation |
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**Can be monitored with AST (?and troponin?) |
**Can be monitored with AST (?and troponin?) |
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*ECG may show ST-T wave changes and first-degree heart block, which can progress to complete heart block |
*ECG may show ST-T wave changes and [[first-degree heart block]], which can progress to [[complete heart block]] |
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**Mortality is higher with ECG changes, and highest with AV blocks and LBBB |
**Mortality is higher with ECG changes, and highest with AV blocks and LBBB |
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**Can be permanent |
**Can be permanent |
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**Followed by cranial nerve defects |
**Followed by cranial nerve defects |
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*After 10 days to 3 months, can develop a peripheral motor neuropathy from demyelination |
*After 10 days to 3 months, can develop a peripheral motor neuropathy from demyelination |
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**Typically descending paralysis by can still be confused with [[Guillain-Barré syndrome]] |
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**Generally fully resolves with time |
**Generally fully resolves with time |
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=====Tubular Necrosis===== |
=====Acute Tubular Necrosis===== |
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*Caused by both the toxin itself and the septic shock |
*Caused by both the toxin itself and the septic shock |
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*Suffocation from aspiration of the pseudomembrane |
*Suffocation from aspiration of the pseudomembrane |
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*Rarely, bacteremia, endocarditis, and arthritis from hematogenous spread |
*Rarely, bacteremia, endocarditis, and arthritis from hematogenous spread |
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*Can have post-infectious, autoimmune-mediated complications including neuropathy and carditis |
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*Mortality 3-12% even now, usually from asphyxiation or myocarditis, but is rare in immunized patients |
*Mortality 3-12% even now, usually from asphyxiation or [[myocarditis]], but is rare in immunized patients |
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===Cutaneous Diphtheria=== |
===Cutaneous Diphtheria=== |
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*Usually caused by non-toxigenic strains |
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*Can also cause chronic non-healing ulcers with dirty-gray membrane, often with concomitant [[Staphylococcus aureus]] or [[Streptococcus pyogenes]] |
*Can also cause chronic non-healing ulcers with dirty-gray membrane (or not), often with concomitant [[Staphylococcus aureus]] or [[Streptococcus pyogenes]] |
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*Generally not invasive and can cause immunity, but also |
*Generally not invasive and can cause immunity, but also contributes to the organism's reservoir |
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===Asymptomatic Carrier State=== |
===Asymptomatic Carrier State=== |
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*Common in areas that do not vaccinate, as well as inner cities and rural areas |
*Common in areas that do not vaccinate, as well as inner cities and rural areas |
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=== |
===Non-Toxigenic Strains=== |
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* |
*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 |
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==Differential Diagnosis== |
==Differential Diagnosis== |
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**Can also collect a piece of pseudomembrane |
**Can also collect a piece of pseudomembrane |
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**Notify lab, who will use modified Tinsdale agar or cystine-tellurite blood agar |
**Notify lab, who will use modified Tinsdale agar or cystine-tellurite blood agar |
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**Gram stain should show classic coryneform "Chinese letter" appearance |
**Gram stain should show classic coryneform "Chinese letter" appearance, which may be dismissed as normal respiratory flora unless specific testing for diphtheria is requested |
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⚫ | |||
*PCR for the toxin gene exists |
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*PCR for the toxin gene exists, and is followed by serology to demonstrate toxin production |
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*Culture |
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*Serology is done for ''tox'' gene positive strains using the Elek test |
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⚫ | |||
==Management== |
==Management== |
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**Preemptive intubation is recommended in most situations |
**Preemptive intubation is recommended in most situations |
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**May require tracheotomy if severe |
**May require tracheotomy if severe |
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**May be useful to add [[carnithine]] to improve myocardial function |
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*If concern for pharyngeal diphtheria, then need to treat presumptively with antitoxin and penicillin while awaiting confirmation of the diagnosis |
*If concern for pharyngeal diphtheria, then need to treat presumptively with antitoxin and penicillin while awaiting confirmation of the diagnosis |
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*Start with with equine-derived diphtheria antitoxin (DAT) |
*Start with with equine-derived diphtheria antitoxin (DAT) |
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*Also treat with a 14-day course of an appropriate antibiotic |
*Also treat with a 14-day course of an appropriate antibiotic |
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**[[Is treated by::Procaine penicillin G]] 600,000 units IM q12h (300,000 units if weight ≤10 kg) |
**[[Is treated by::Procaine penicillin G]] 600,000 units IM q12h (300,000 units if weight ≤10 kg) |
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***Can switch or oral penicillin once able to take oral medication |
***Can switch or oral [[penicillin]] once able to take oral medication |
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**[[Is treated by::Erythromycin]] 40 mg/kg/day (max 2 g) PO/IV divided qid |
**[[Is treated by::Erythromycin]] 40 mg/kg/day (max 2 g) PO/IV divided qid |
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*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 |
*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 |
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**If still positive, extend treatment for another 10 days |
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*After acute illness, still need to vaccinate since infection does not generate long-term immunity |
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===Cutaneous Diphtheria=== |
===Cutaneous Diphtheria=== |
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*Indicated for healthcare workers exposed to nasopharyngeal secretions, household contacts, other habitual close contacts, people sharing utensils or kitchen facilities, and childcare workers |
*Indicated for healthcare workers exposed to nasopharyngeal secretions, household contacts, other habitual close contacts, people sharing utensils or kitchen facilities, and childcare workers |
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**Indicated ''regardless of'' immunization status |
**Indicated ''regardless of'' immunization status |
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**Even if the contact is transient, but excludes those who were wearing appropriate PPE at the time |
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*Procedure |
*Procedure |
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**Monitor for symptoms for 7 days |
**Monitor for symptoms for 7 days |
Revision as of 14:50, 26 November 2020
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 species
- 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
- Procaine penicillin G 600,000 units IM q12h (300,000 units if weight ≤10 kg)
- 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