Disease is caused by exotoxin which inhibits protein synthesis of eukaryotic cells

· The exotoxin is absorbed into the blood stream and distributed, resulting in systemic complications

o demyelinating neuritis

o myocarditis.

· The diphtheria toxin also causes local destruction at the site ofmembrane formation.

o The toxin contains a toxic A subunit (active toxin)and the receptor binding B subunit.

o Fragment B attaches to cellular receptors and grants fragment A entrance into the cell, where it inhibits protein synthesis.

§ The B subunit (fragment)facilitates translocation of the A subunit from the phagosome to the cytosol, followed by separation, allowing full activity of the A subunit on its target protein elongation factor-2. EF-2 transfers polypeptidyl-transfer RNA from acceptor to donor sites on the ribosome of the host cell.

§ The A subunit catalyzes transfer of adenine ribose phosphate from NAD to EF-2 (ADP ribosylation), inactivating EF-2, and turning off protein synthesis, C. diphtheria toxin is able to inhibit protein synthesis of all eukaryotic cells.

§ Fragment A has the enzymatic activity

Describe the toxin gene of Corynebacterium diphtheriae

The answer

· Gene for the diphtheria toxin is carried in genome of a bacteriophage.

· C. diphtheria strains must contain a bacteriophage (beta-phage), acquired by transduction from other C. diphtheria strains, in order to express the toxin.

· The phage must be Iysogenized following transduction.

· The toxin expression (fox gene) is regulated by a chromosomally encoded repressor protein (DtxR) when iron is limited.

What defenses humans have against Corynebacterium diphtheriae?

The answer

• We don't seem to have any protection against the toxin.
• Protection is ensured only by vaccination.

What are the clinical manifestations of diphtheria? What is the end result of this battle between organisms and humans. Describe the pathological consequences of this battle?

The answer

Incubation period is 2-5 days

Diphtheria is the result of local and systemic effects of diphtheria toxin.

• Local
• A "membrane" forms in throat. It is a coagulum of fibrin, leukocytes, cellular debris due to local cytotoxicity by the toxin.
• The membrane can extend from the oropharynx to larynx and into the trachea.
• Sore throat, hoarseness and dysphagia follows.
• Respiratory diphtheria may progress rapidly.
• Respiratory arrest may occur from airway obstruction with tracheobronchial membrane.
• Cough, strider wheezing are the result.

· Systemic

o Diphtheria toxin can circulate in blood and affect heart and CNS systems.

§ Myocarditis, with cardiac enlargement, circulatory collapse, heart failure, AV blocks and dysrhythmias.

• Nervous system can also be involved including paralysis of soft palate, oculomotor dysfunction. They resolve with resolution of infection.
• Fever and chills, malaise, cervical adenopathy, nausea and vomiting.

What is the natural history of untreated infection with Corynebacterium diphtheriae?

The answer

• Mortality in untreated cases is 10-50%.

How can we diagnose diphtheria?

The answer

· Initial diagnosis is clinical

· No rapid lab test

· Gram stain of throat not helpful

· Organism can be cultured to confirm diagnosis.

o Missed on routine cultures.

o Notify the lab of possible diagnosis

· Toxin production of cultured strains can be performed by immunodiffusion.

· Serum for antibodies to diphtheria toxin

Other useful evaluations

· EKG and Cardiac enzymes to detect myocarditis

· CXR: Hyperinflation, subglottic narrowing

What will be your therapeutic strategy for diphtheria?

The answer

· Strict isolation

· C. diphtheriae antitoxin is given promptly to neutralize free toxin.

o Contact CDC for antitoxin and instructions on use.

o Do not wait for culture confirmation.

o Antibodies produced against the toxin in natural infection.

o Treat with toxin to neutralize free toxin before it binds to cells.

· The organism itself can be treated with penicillin, cephalosporins, and erythromycin.

· Notify the health department

· Clinical diphtheria does not confer immunity, hence active immunization with diphtheria toxoid should be provided during convalescence.

· Supportive care

o Bronchodilators if needed.

o Watch for respiratory obstruction and take necessary steps.

o Watch for myocarditis and mange appropriately

How can you prevent its occurrence of diphtheria? How can you prevent it from spreading to others? How can you prevent its recurrence?

The answer

• Strict isolation of cases
• Notify the health department of cases
• Surveillancein communities where Diphtheria is endemic
• Timely vaccination
• Diphtheria: Immunization with toxoid elicits an antibody response that prevents diphtheria infection.
• Vaccination with toxoid=formalin treated toxin
• Booster doseof Tetanus-Diphtheria every 10 years through adulthood
• Close contacts
• Should be identified and treated with oral erythromycin for 7-10 days
• Provide active immunization
• Clinical diphtheria does not confer immunity, hence active immunization with diphtheria toxoid should be provided during convalescence.

What are the clinical infections of other species ofCorynebacterium?

The answer

Corynebacterium ulcerans:

• Cutaneous Diphtheria
• Generally caused by tox-strains.
• Produces natural immunity
• Can cause epidemics in poorly immunized populations.

Prevention

Before antibiotics were available, diphtheria was a common illness in young children. Today, the disease is not only treatable but also preventable with a vaccine.

The diphtheria vaccine is usually combined with vaccines for tetanus and whooping cough (pertussis). Tetanus is a bacterial infection that leads to stiffness of the jaw and other muscles. Whooping cough is a bacterial infection of the respiratory tract. The three-in-one vaccine is known as the diphtheria, tetanus and pertussis, or DTP, vaccine. The latest version of this immunization is known as the DTaP vaccine.

The diphtheria, tetanus and pertussis vaccine is one of the childhood immunizations that doctors in the United States recommend begin during infancy. The vaccine consists of a series of five shots, typically administered in the arm or thigh, and is given to children at ages:

§ 2 months

§ 4 months

§ 6 months

§ 15 to 18 months

§ 4 to 6 years

The diphtheria vaccine is very effective at preventing diphtheria. But there may be some side effects. Some children may experience a mild fever, fussiness, drowsiness or tenderness at the site of the injection after a diphtheria, tetanus and pertussis shot. Ask your doctor what you can do for your child to minimize or relieve these effects.

Rarely, the diphtheria, tetanus and pertussis vaccine causes serious complications in a child, such as an allergic reaction (hives or a rash develops within minutes of the injection), seizures or shock — complications which are treatable.

Some children — such as those with progressive brain disorders — may not be candidates for the diphtheria, tetanus and pertussis vaccine. But, the number of children to whom these restrictions apply is small.

You can't get diphtheria from the vaccine.

Booster shots
After the initial series of immunizations in childhood, booster shots of the diphtheria vaccine are needed to help you maintain immunity. That's because immunity to diphtheria fades with time.

The first booster shot is needed around age 12, and then every 10 years after that — especially if you travel to an area where diphtheria is common. Ask your doctor whether you're up-to-date on your immunizations. Be sure your child is as up-to-date as possible on childhood vaccinations before starting child care or school.

A booster shot of the diphtheria vaccine is given in combination with a booster shot of the tetanus vaccine. The tetanus-diphtheria (Td) vaccine is given by injection, usually into the arm or thigh.

Doctors recommend that anyone older than age of 7 who has never been vaccinated against diphtheria receive three doses of the Td vaccine.