View source for 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, [[Shape::pleomorphic]], unencapsulated, nonmotile [[Stain::Gram-positive]] [[Shape::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 [[Corynebacterium species|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 ''[[Corynebacterium ulcerans|C. ulcerans]]''
*Incubation period of [[Usual incubation period::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
**[[Is treated by::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
**[[Is treated by::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

{{DISPLAYTITLE:''Corynebacterium diphtheriae''}}
[[Category:Gram-positive bacilli]]