DIPHTHERIA

By Dr. Omayo
14/10/2014
 Introduction

• Diphtheria is responsible for both endemic and epidemic diseases.

• It was first described in the 5th century BC by Hippocrates.

• Diphtheria manifests as either localized upper respiratory tract infection,

localized cutaneous infection and rarely systemic infection.

• It is caused by Corynebacterium diphtheria.

• It is communicable for 2-6 weeks without antibiotic treatment.

There are 3 isolated strains of C diphtheria:

1. Gravis

2. Intermedius

3. Mitis.

Intermedius is thought to be responsible for systemic elaboration of the disease,

as it is most often associated with the exotoxin.

However, all 3 strains are capable of producing toxins.

 Epidemiology
International

•According to the World Health Organization (WHO), diphtheria epidemics remain

a health threat in developing nation.

•The largest epidemic recorded since widespread implementation of vaccine

programs was in 1990-1995, when a diphtheria epidemic emerged in the Russian
Federation, rapidly spreading to involve all Newly Independent States (NIS) and
Baltic States. This epidemic caused more than 157,000 cases and 5000 deaths
according to WHO reports.

•Overall rates of infection have decreased in Europe from 2000 to 2009, according
to the Diphtheria Surveillance Network. This has been attributed to improved
vaccination rates creating herd immunity. However, issues with vaccinations still
occur, especially in eastern European countries and Russia, and are thought to
contribute to the ongoing outbreaks.

•Many case reports in the literature describe epidemics in sub-Saharan Africa,

France, India, and the United States.
 Epidemiology cont.
Mortality/Morbidity

•Before the introduction of vaccine in the 1920s, the incidence of respiratory

disease was 100-200 cases per 100,000 population in the United States and
has decreased to approximately 0.001 cases per 100,000 population.

•The most widely quoted diphtheria mortality rate is 5-10%. It may reach
higher than 20% in children younger than 5 years and adults older than 40
years.

•Immunization patterns have the most influence on mortality patterns.

Mortality rates have not changed significantly over the past few decades.

•Most deaths occur on days 3-4 secondary to asphyxia with a pharyngeal

membrane or due to myocarditis.
 Epidemiology cont.
Age
•Diphtheria has been primarily a disease of childhood, affecting populations
younger than 12 years.

•Infants become susceptible to the disease at age 6-12 months after their
transplacentally derived immunity wanes.

•Since the advent of diphtheria vaccination, cases of pediatric disease have

declined dramatically.

• Recently, however, diphtheria has shifted into the adolescent and adult
population, most notably in ages 40 and older accounting for most new cases.
This is due to incomplete immunization status, including never being
immunized and not receiving a booster after previous vaccination.
• According to immunologic studies, one must have an antitoxin level of greater 0.1
IU/mL for adequate immunity.

• Immunization schedules have recently changed requiring a toxoid booster at age

11-12 and every 10 years thereafter.

• The toxoid booster, without tetanus, is approved for pregnant women if their
antitoxin titers are less than 0.1 IU/mL.
 Presentation

Respiratory diphtheria

•Onset of symptoms typically follows an incubation period of 2-5 days (range,

1-10 d).

•Symptoms initially are general and nonspecific, often resembling a typical

viral upper respiratory infection (URI). Begins with a sore throat and mild
pharyngeal inflammation.

•Development of a localized or coalescing pseudomembrane occurs in any

portion of the respiratory tract. The pseudomembrane is characterized by the
formation of a dense, gray debris layer composed of a mixture of dead cells,
fibrin, RBCs, WBCs, and organisms.
 Presentation cont.

• Removal of the membrane reveals a bleeding, edematous mucosa.

• The distribution of the membrane varies from local (e.g, tonsillar,

pharyngeal) to widely covering the entire tracheobronchial tree.

• The membrane is intensely infectious, and droplet and contact precautions

must be followed when examining or caring for infected patients.

• A combination of cervical adenopathy and swollen mucosa imparts a

"bull's neck" appearance to many of the infected patients.

• The most frequent cause of death is airway obstruction or suffocation

following aspiration of the pseudomembrane into the tracheobronchial tree.
The characteristic thick membrane of diphtheria infection in the posterior
pharynx.
Cervical edema and cervical lymphadenopathy from diphtheria
infection produce a bull's neck appearance in this child.
 Presentation cont.
2. Cutaneous diphtheria

•Characterized by indolent, nonhealing ulcers covered with a gray membrane.

•The ulcers are often co-infected with Staphylococcus aureus and group A
streptococci. This form of the disease is seen with increasing frequency in
poor inner-city dwellers and alcoholics.

•The lesions of cutaneous diphtheria are infectious, and bacteria from

cutaneous lesions have been found to cause pharyngeal infections and thus
serve as a reservoir for infection.

•Cutaneous diphtheria often develops at a site of previous trauma or a primary

dermatologic disease.

•It follows an indolent course, typically lasting weeks to months.

 Symptoms
• Patients present with:

1. Low-grade fever and chills

2. Malaise, weakness, prostration

3. Sore throat (85-90%)

4. Headache

5. Cervical lymphadenopathy and respiratory tract pseudomembrane

formation (about 50%)

6. Serosanguineous or seropurulent nasal discharge, white nasal membrane

7. Hoarseness, dysphagia (26-40%)

8. Dyspnea, respiratory stridor, wheezing, cough

 Physical examination
1. General: Patient has a low-grade fever but is toxic in appearance, and
also may have a swollen neck.

2. Pharyngeal diphtheria: Fever, halitosis, tachycardia, and anxiety.

3. Tonsils and pharynx: Pharyngeal erythema and edema, thick, gray,

leathery membrane variably covers the tonsils, soft palate, oropharynx,
nasopharynx, and uvula. Attempts at scraping the pseudomembrane
causes bleeding of the underlying mucosa.

4. Neck: Extensive anterior and submandibular cervical lymphadenopathy

imparts a bull's neck appearance. The patient may hold his or her head in
extension. It can occasionally also be associated with dysphonia.

5. Respiratory distress manifesting as stridor, wheezing, cyanosis, accessory

muscle use, and retractions.
 Physical examination cont.

Cardiac toxicity

Occurs after 1-2 weeks of illness following improvement in the pharyngeal

phase of the disease.

 It may manifest as follows:

•Myocarditis is seen in as many as 60% of patients (especially if previously

unimmunized) and can present acutely with congestive heart failure (CHF),
circulatory collapse, progressive dyspnea, diminished heart sounds.

•Atrioventricular blocks, ST-T wave changes, various dysrhythmias.

 Physical examination cont.
Neurologic toxicity

Most patients with severe disease develop neuropathy.

Most C diphtheriae associated neurologic dysfunction eventually resolves.
Deficits include the following:

•Cranial nerve deficits including oculomotor, ciliary paralysis, facial, and

pharyngeal, or laryngeal nervous dysfunction.

•Occasionally, a stocking and glove peripheral sensory neuropathy pattern can

be observed.

•Peripheral neuritis develops anywhere from 10 days to 3 months after the

onset of pharyngeal disease. It manifests initially as a motor defect of the
proximal muscle groups in the extremities extending distally.
 Physical examination cont.

• Cutaneous diphtheria begins as a painful lesion resembling an

erythematous pustule, which breaks down to form an ulcer covered with a
gray membrane.
 Differential Diagnoses

• Epiglottitis
• Peritonsillar Abscess
• Pharyngitis
• Retropharyngeal Abscess
• Rheumatic Fever
• Septic shock(Rare)
• Angioedema
• Endocarditis
• Mononucleosis
• Myocarditis
• Oropharyngeal/esophageal candidiasis
 Complications
• Respiratory failure due to pseudomembrane formation or aspiration, tissue
edema, and necrosis

• Cardiac - Myocarditis, cardiac dilatation and failure, mycotic aneurysm,

endocarditis

• Rhythm disturbances - Heart block, including AV dissociation and

dysrhythmias

• Secondary bacterial pneumonia

• Cranial nerve dysfunction and peripheral neuropathy, total paralysis

• Optic neuritis

• Septicemia/shock

• Death
 Prognosis

• Cardiac involvement is associated with a very a poor prognosis,

particularly AV and left bundle-branch blocks (mortality rate 60-90%).

• Bacteremic disease carries a mortality rate of 30-40%.

• High mortality rates are seen in individuals younger than 5 years and in
those older than 40 years.
 Investigation
Bacteriologic testing

•Gram stain shows club-shaped, nonencapsulated, nonmotile bacilli found in

clusters.

•Immunofluorescent staining of 4-hour cultures or methylene blue–stained

specimen may sometimes allow for a speedy identification.

Cultures

•With swabs taken from the nose, pseudomembrane, tonsillar crypts, any
ulcerations, or discolorations. Identification is accomplished through
observation of colony morphology, microscopic appearance, and fermentation
reactions.

•Any diphtheria bacilli isolated must be tested for toxin production.

 Investigation
Toxigenicity
•Toxigenicity testing is aimed to determine the presence of toxin production.

•Elek test detects the development of an immunoprecipitin band on a filter paper

impregnated with antitoxin and then is laid over an agar culture of the organism being
tested.

•Polymerase chain reaction (PCR) assays for detection of DNA sequence encoding
the A subunit of tox+ strain are both rapid and sensitive.

•Once diphtheria infection has been established, the Centers for Disease Control and
Prevention (CDC) should be contacted, and further testing may be requested.
Other laboratory studies

•CBC may show moderate leukocytosis.

•Urinalysis (UA) may demonstrate transient proteinuria.

•Serum antibodies to diphtheria toxin prior to administration of antitoxin: Low levels

cannot exclude the possibility of the disease; high levels may protect against severe
illness (concentrations of 0.1 to 0.01 IU are thought to confer protection).

•Serum troponin I levels seem to correlate with the severity of myocarditis.

• Chest radiograph and soft tissue neck radiography/CT or ultrasonography may
show prevertebral soft tissue swelling, enlarged epiglottis, and narrowing of the
subglottic region.

• ECG may show ST-T wave changes, variable heart block, and dysrhythmia
 Management
• Secure definite airway for patients with impending respiratory
compromise. Consider involving ENT or operating room personnel for
intubation and securing of airway if there is suspicion for loss of the
airway or respiratory failure.

• Maintain close monitoring of cardiac activity for early detection of rhythm

abnormalities.

• Provide 2 large-bore IVs for patients with a toxic appearance.

• Antipyretics for fever.

• Patients with active disease as well as all close contacts should be treated
with antibiotics. This entails treatment with erythromycin or penicillin for
14 days and post treatment cultures to confirm eradication.

• Treatment is most effective in the early stages of disease and decreases the
transmissibility and improves the course of diphtheria.
• The CDC has approved macrolides such as erythromycin as first-line agents for
patients older than 6 months of age.

• Intramuscular penicillin is recommended for patients who will be noncompliant

or intolerant to an erythromycin course.

• The horse serum antitoxin is given to anyone suspected to have diphtheria and
can be administered without confirmation from cultures, as it is most efficacious
early during the course of the disease. Diphtheria antitoxin neutralizes toxin
before it enters cells. Dose given depends on site of infection and length of time
patient is symptomatic.
 Follow up
• Observe for development of primary or secondary bacterial pneumonia.

• Perform serial ECGs to detect cardiac abnormalities.

• Provide physical therapy for patients with neurologic dysfunction.

• Patients with endocarditis may require valve replacement, especially with

previous prosthetic valves.

• Monitor for serum sickness or hypersensitivity reactions in patients treated

with DAT.

• Complete age-appropriate immunization schedule.

• Follow-up pharyngeal cultures post treatment, confirming eradication of the

bacterium. 2 weeks post treatment.
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