Corynebacterium diphtheriae

Diphtheria

Summary
Diphtheria is an infectious disease caused by Corynebacterium diphtheriae, which is usually
transmitted via respiratory droplets. The clinical features of diphtheria are caused by a toxin
produced by C. diphtheriae after it colonizes the upper respiratory tract. Patients initially
present with fever, malaise, and sore throat. Within a few days, a grayish white
pseudomembrane develops over the tonsils, posterior pharyngeal wall, and/or larynx. Other
manifestations include cervical lymphadenopathy, soft tissue swelling of the neck, stridor,
and/or difficulty breathing as a result of partial airway obstruction. Systemic absorption of the
toxin can result in myocarditis, acute tubular necrosis, and/or polyneuropathy. Even before
culture reports come back positive, patients should be promptly treated with penicillin and
antitoxins, as untreated diphtheria is associated with a high mortality rate. Since the
introduction of routine immunization against diphtheria in the 1920s, the incidence of disease
has decreased dramatically in the US.

Epidemiology
 Incidence: 0–5 cases/year 
 Most cases occur in patients 20 years of age or older. 
Epidemiological data refers to the US, unless otherwise specified.

Etiology
 Pathogen: Corynebacterium diphtheriae
 A gram-positive, non-sporulating, club-shaped bacillus,
containing metachromatic granules (AKA volutin granules). 
 Route of infection 
 Droplet transmission
 Less commonly through direct or indirect contact with open lesions (see extra
information for more details on cutaneous diphtheria)
 Infectious period: variable 
Pathophysiology
 C. diphtheriae colonizes the mucous membrane of the respiratory tract (respiratory
diphtheria) 
 C. diphtheriae has both toxigenic and non-toxigenic strains; toxigenic strains contain
a prophage gene called tox, which encodes the diphtheria toxin, an exotoxin that
inhibits protein synthesis by ADP-ribosylation and deactivation of EF-2 
 Local effects of the toxin: destruction of the respiratory epithelium →
inflammatory response →
 Necrotic epithelium embedded
within fibrinosuppurative inflammatory exudate (pseudomembrane) over
the pharynx, tonsils, and/or larynx
 Enlargement of the cervical lymph nodes and edema of the soft tissue
of the neck → bull neck appearance, airway obstruction
 Systemic effects of the toxin 
 Fatty changes and focal necrosis of the myocardium and less
commonly, the liver, kidney, and adrenal glands
 Nerve demyelination

Clinical features

Respiratory diphtheria
 Incubation period: 2–5 days
 The patient presents initially with prodromal symptoms: fever, malaise, and sore
throat
 4–5 days after the onset of prodromal symptoms, symptoms due to the local and
systemic effects of the toxin occur
 Local features
 Anterior nasal diphtheria: bloody rhinorrhea
 Tonsillar and pharyngeal diphtheria
 A grayish white pseudomembrane over
the posterior pharyngeal wall, and/or tonsils
 Any attempt to scrape off the pseudomembrane exposes the
underlying capillaries and results in heavy bleeding.
 Bull neck, which may result in airway obstruction 
 Foul mouth odor
 Laryngeal diphtheria: difficulty breathing, inspiratory stridor 
 Systemic features
 Myocarditis → arrhythmias
 Reversible polyneuropathy
Cutaneous diphtheria
 Cutaneous diphtheria is the result of direct inoculation of C. diphtheriae into skin
(e.g., skin abrasions) or pre-existing skin lesions. 
 Cutaneous diphtheria is usually seen in tropical regions, where it is more common
than respiratory diphtheria. 
 Patients present with scaly erythematous rash, impetigo, or deep, punched-out ulcers 
 Cutaneous diphtheria does not result in systemic effects. 

Diagnostics
 Cultures of pharyngeal swabs are used to confirm the diagnosis 
 Microscopic examination of pharyngeal swabs or culture isolates reveals
multiple C. diphtheriae clustered together. 
 Culture media of choice are cystine-tellurite agar or Löffler medium or
tinsdale medium.
 Once the culture reveals C. diphtheriae, one or both of the following tests are used to
identify whether the strain is toxigenic:
 Elek's test 
 Polymerase chain reaction to identify the tox gene
 Test for myocarditis: Conduct multiple ECGs and serial measurement of cardiac
markers. 
Figure : 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.

Therapy should be started immediately upon clinical suspicion, even before diagnostic
confirmation of diphtheria!

Differential diagnoses
 See differential diagnosis of acute tonsillitis
 See differential diagnosis of croup
 Oropharyngeal candidiasis

Treatment
 The patient should be isolated as soon as diphtheria is suspected. 
 Antibiotic therapy : IM injections of Penicillin G or oral/IV erythromycin for 14 days
 Immediate administration of diphtheria antitoxin: The antitoxin can only neutralize
unbound toxin and should therefore be administered early in the course of the
disease. 
 Airway support 
Administration of the antitoxin is a critical part of treatment, as the clinical features of
diphtheria are not caused by the pathogen itself but rather by the exotoxin that C.
diphtheriae produces!
Prevention

Pre-exposure prophylaxis
 Toxoid vaccine
 In the US, four vaccines are available to prevent diphtheria: DTaP, Tdap, DT, and Td
(see immunization schedule).

Post-exposure prophylaxis
Post-exposure prophylaxis is indicated for close personal contacts and caretakers of a patient
with diphtheria.
 Erythromycin or a single dose of benzathine penicillin
 Complete immunization schedule if vaccinations are not up-to-date.
Diphtheria is a notifiable disease!

Bordetella pertussis.

Pertussis (Whooping cough…)

Summary
Pertussis, or whooping cough, is a highly infectious disease of the respiratory tract caused by
the gram-negative bacteria Bordetella pertussis. The disease is mainly transmitted via
airborne droplets and is most commonly occurs in children. Typically, pertussis manifests in
three stages, with the second and third stage characterized by an
intense paroxysmal coughing that is followed by a distinctive whooping sound on inhalation
and, in some cases, vomiting. Young infants may not develop the typical cough, and often
present with apnea and cyanosis instead. The disease is most often diagnosed via laboratory
tests, especially detection of B. pertussis in bacterial culture. However, as test results may
take time to obtain, treatment should be initiated as soon as clinical suspicion of pertussis
arises. Subsequent management includes hospitalization of high-risk patients (e.g., infants)
and antibiotic therapy with macrolides. These may lessen the length and severity of the
disease if administered early, while also reducing infectivity and further disease
transmission. Macrolides are also the drug of choice for post-exposure prophylaxis (PEP),
which is recommended for all people with a recent history of exposure to pertussis. PEP is
administered regardless of the individual immunization status, as both vaccination and prior
infection may shorten the disease course, but do not provide full immunity.

Epidemiology
 Typically a childhood disease (particularly children aged < 1 year); however, older
patients are increasingly affected
 High rate of infections in newborns: no transfer of maternal immunity (passive
immunity)

Etiology
 Pathogen: Bordetella pertussis is a gram-negative, obligate aerobic coccobacillus
 Transmission: airborne droplet (through coughing); direct contact with oral or nasal
secretions
 Infectivity
 Without antibiotic treatment: 4–6 weeks
 With treatment: ∼ 5 days
 Highly virulent 
 Incubation period: on average 7–10 days

Pathophysiology
 Bordetella pertussis proliferates on ciliated epithelial cells of the respiratory mucosa
→ produces virulence factors → paralyze cilia of respiratory epithelium and
cause inflammation → inflammatory exudate secreted into respiratory tract →
compromises small airways → cough, pneumonia, cyanosis
 Bordetella pertussis produces pertussis toxin → catalyzes the ADP-ribosylation of
the α subunit of G  protein , thereby impairing it → adenylate cyclase activity is no
i

longer inhibited by G protein → leads to accumulation of cAMP → impairs cell

i 

signaling pathways
 Pertussis toxin is responsible for most of the systemic manifestations
associated with whooping cough (e.g. hypoglycemia, lymphocytosis, modulation of
host immune response)
 Neither vaccination nor actual infection confer lifelong or complete immunity.

Stages

Catarrhal stage (∼ 1–2 weeks)

 Nonspecific symptoms similar to an upper respiratory infection (mild cough,
watery nasal discharge, rarely low-grade fever)
 Possibly conjunctivitis

Paroxysmal stage (∼ 2–6 weeks)

 Intense paroxysmal coughing (often occurring at night)
 Followed by a deep and loud inhalation or high-pitched “whooping” sound
  Accompanied by tongue protrusion , gagging, and struggling for breath
 Possibly accompanied by cyanosis
 Increases in frequency and severity throughout the stage
 Followed by the expulsion of phlegm or posttussive vomiting (risk of dehydration)
 In infants (< 6 months): risk of apnea; infants may not develop the
typical cough and only manifest with apnea → close monitoring necessary!

Convalescent stage (weeks to months)

 Progressive reduction of symptoms
 Coughing attacks may persist over several weeks before resolving
The typical whooping cough manifests mainly in children aged 6 months to 5 years. The
disease stages may be indistinguishable in young infants and adults!

Diagnostics
A presumptive diagnosis of pertussis may be made based on clinical history and findings.
However, if possible, laboratory tests should be performed to confirm the diagnosis.

History
 Clinical diagnosis possible in patients with a cough lasting ≥ 2 weeks and at least one
of the following symptoms:
 Coughing paroxysms
 Whoop on inspiration
 Vomiting following coughing attack
 Apnea (in infants)
 Inquire about immunization history and possible contact with infectious persons.

Laboratory tests
 Blood count: lymphocyte-predominant leukocytosis (50,000–60,000/μL) that
corresponds with disease severity 
 Pathogen detection (to confirm the diagnosis)
 Culture (gold standard) or PCR: samples from deep
nasopharyngeal aspiration or posterior nasopharyngeal swab 
As B. pertussis only grows on respiratory epithelium, blood cultures are always negative!

Differential diagnoses
 Bordetella parapertussis infection 
 Respiratory syncytial virus bronchiolitis
 Pneumonia, particularly due to Chlamydia trachomatis or Mycoplasma pneumoniae
 Croup (laryngotracheobronchitis)
 Foreign body aspiration

Treatment

General approach
  Early initiation of treatment, especially in high-risk patients (e.g., infants), while
confirmatory laboratory tests are pending
 Hospitalization and monitoring: infants < 4 months; severe cases (e.g., respiratory
distress, cyanosis, apnea, inability to feed)
 Oxygen administration with humidification
 Increased fluid intake and nutritional support 
 If necessary, sedation

Medical therapy
 Macrolides (e.g., azithromycin, clarithromycin, erythromycin)
 In children > 1 month and adults: any macrolide 
 Alternative if macrolides are not tolerated: trimethroprim-
sulfamethoxazole
 Infants < 1 month: azithromycin 
 Early administration may lessen symptoms of the catarrhal stage and
early paroxysmal stage.
 Late antibiotic administration has little influence on disease severity but
reduces infectivity.

Complications
 Infections: otitis media, pneumonia
 Pulmonary: atelectasis, pneumothorax 
 Neurologic: seizures, encephalopathy wih possible permanent damage 

Prognosis
 In children > 3 months: very good; lengthy convalescence, but full recovery
 In children < 3 months: mortality 1–3%, particularly due to apnea
 Increased risk for complications: premature infants; children < 6 months; people with
underlying cardiac, pulmonary, neurologic, or neuromuscular disease

Prevention
 Immunization
 Children
 Routine immunization: administer DTaP vaccine (diphtheria, tetanus,
and pertussis) at 2, 4, 6, and 15–18 months, as well as 4–6 years (see immunization
schedule)
 Booster vaccination: administer Tdap vaccine: 
 Single dose at 7–10 years of age if immunization is
incomplete; 
 Single-dose boost at 11–18 years of age, at least 10
years following the last dose 
 Contraindications: known anaphylactic
reactions, encephalopathy following previous vaccination 
 Adults
 One-time dose of Tdap
 In particular, pregnant women  and people in contact
with newborns should be vaccinated! → increases passive immunity
 Post-exposure prophylaxis: choice of antibiotics identical to treatment
recommendations (see “Therapy” above)
 Household and close contacts of infected people; especially people at risk of
developing complications or close contacts of high-risk individuals (see
“Complications” above)
 Administered regardless of immunization status
 Isolation: for 5 days after initiation of antibiotic therapy
 Reporting: Pertussis is a notifiable disease