Diphtheria

1. Causative Organism
2. Clinical Signs, Symptoms and Complications
3. Method of Transmission
4. Public Health Significance
5. Prevention - Non Immunisation Methods
6. Prevention - Immunisation
7. Vaccine/s and Vaccination
8. Efficacy and Effectiveness
9. Availability
10. Dosage and Administration
11. Adverse Events
12. Contraindications
13. Risks vs Benefits

Causative Organism

The bacteria Corynebacterium diphtheriae causes diphtheria. The toxin produced by some diphtheria bacteria can cause serious and life-threatening infections.

Signs, Symptoms and Complications

• Membranous inflammation of the upper respiratory tract and nasopharynx, which may cause hoarseness, loss of voice or stridor (greyish membrane with a characteristic mousy smell). This may be accompanied by mildly painful tonsillitis or pharyngitis (90%).
• Lymphadenopathy may lead to a “bull neck” appearance and the angle of the jaw may be obliterated. Unilateral or bilateral paralysis of the palatal muscles may lead to dysphagia.
• Skin and mucous membrane (mouth, vagina) lesions may occur in less serious disease. Pain, tenderness, and erythema at the site of infection progresses to ulceration with sharply defined borders and formation of a brownish grey membrane.
• Infection by toxigenic strains may lead to toxin release, which can cause myocarditis, peripheral neuropathy with flaccid paralysis, renal failure secondary to tubular necrosis, stupor, coma and death.
• 10% of patients die of mechanical airway obstruction or circulatory collapse.
  

Child has diphtheria, thick grey coating over back of throat. Courtesy of Centers for Disease Control and Prevention.

Method of Transmission

• Humans are the only known reservoir of diphtheria. The discharge from an infected person’s nose, throat, eye and skin lesions contains the bacteria and is contagious.
• Transmission mostly happens from intimate contact with an infected person although fomites and food-borne sources can serve as vehicles of transmission.

Public Health Significance

• Diphtheria is rare in industrialised countries where immunisation programmes have run for decades. However, it's still common in some countries.
• Since 1990, epidemic diphtheria has re-occurred through the Newly Independent States (NIS) of the former Soviet Union, including Russia, the Ukraine and the central Asian republics. In the 6 years from 1990 through 1995, the NIS accounted for more than 90% of all diphtheria cases reported to the World Health Organization from the entire world.
• Illness is most common in low socio-economic groups living in crowded conditions. Infection can occur in immunised and partially immunised people, but disease is most severe in people who are not immunised.
• Antibiotic treatment usually renders patients non-infectious within 24 hours.
• An estimated 20% of those under 20 and 75% of those over 65 worldwide are thought to have insufficient immunity to diphtheria due to inadequate immunisation coverage and waning immunity.
• While immunisation leads to the disappearance of toxigenic strains, non-toxigenic strains may become toxigenic through phage transmission. This makes the possibility of a resurgent diphtheria epidemic a real threat wherever there is insufficient community (herd) immunity.

New Zealand Epidemiology

Between 1917 and 1921 there were 794 reported deaths in non-Maori from diphtheria. Regular epidemics of infection occurred in New Zealand until 1950, and further outbreaks occurred in Milton and the Waikato in the 1960s. In 1998 the first case of diphtheria was reported in New Zealand since 1979, and this was the first toxigenic isolate since 1987. In 2002 a four-year-old child was reported after a toxigenic strain was isolated from a hip aspirate. The child had no toxin related symptoms and had been fully vaccinated for age; this would not be regarded as a vaccine failure.

There is no current data on the proportion of New Zealand adults susceptible to diphtheria. The 1985 National Serum Survey found that 73 percent of five year olds, 65 percent of 10 year olds and 53 percent of 15 year olds had protective levels of diphtheria antibody. The decline apparent with age suggests that there is likely to be a large and increasing pool of adults susceptible to diphtheria in New Zealand. This was the reason for the introduction of adult tetanus diphtheria (Td) vaccination in 1994. (Immunisation Handbook 2006, Ministry of Health.)

Prevention - Non Immunisation Methods

•  Isolation of cases.
• Pharyngeal culture and prophylactic erythromycin for close contacts.

Prevention - Immunisation

Immunisation remains the only well-established mode of disease prevention.

Diphtheria vaccination has been widely offered since World War II, leading to virtual disappearance of the disease in many countries. Consequently, there is little opportunity to acquire natural immunity. Local health officials should be notified when cases of diphtheria occur. Public health measures include isolation of the contagious person and contact tracing to identify additional people who may be infected or at risk of infection.

Vaccine/s and Vaccination

Diphtheria vaccine is a modified toxin. To produce the vaccine, diphtheria bacteria are cultured to produce toxins that are then detoxified with formaldehyde to form toxoids. The toxoids are attached to either aluminium hydroxide or aluminium phosphate as adjuvants to stimulate the immune response. In countries with developed economies, these are usually provided as a combination vaccine with tetanus, pertussis, polio, hepatitis B and/or Hib. 

Efficacy and Effectiveness

• The vaccine offers good protection against diphtheria (field efficacy of 87-98%). People who have been immunised against diphtheria may still carry the organism in their throats and can still pass the infection on to unimmunised people and young babies.
• Complete immunisation induces protective levels of antitoxin lasting throughout childhood, but by middle age about 50% of vaccinated people have low levels of antitoxin circulating. Clinical studies have demonstrated that a single dose of toxoid in previously immunised adults induces protective levels within 6 weeks.
  

Availability

• In New Zealand, the diphtheria vaccine is only available as a component of a combination vaccine. The diptheria, tetanus, acellular pertussis and inactivated polio vaccine.  The publicly funded vaccine for the infant series and the booster is the diphtheria, tetanus, acellular pertussis and inactivated polio vaccine (DTaP-IPV-HepB/Hib Infanrix™-Hexa, GSK).
• A smaller adult dose of diphtheria and pertussis vaccine together with tetanus and inactivated polio vaccine (dTap Boostrix^®, GSK) is also available. (Immunisation Handbook 2006, Ministry of Health.)
• The other diphtheria vaccines available that is publicly funded is ADT-Booster®, for those requiring an alternative to a pertussis containing vaccine.
• Most countries with developed economies have a variety of combination formulations available.

Dosage and Administration

•  In New Zealand, DTaP-IPV-HepB/Hib (Infanrix^®-hexa, GSK) is given at six weeks, three months and five months. A booster DTaP-IPV (Infanrix™-IPV, GSK) is given at four years.
•  dTap (Boostrix^®, GSK)  is given at 11 years of age.

Contacts of cases:  in addition to isolation (including exclusion from school or day care), pharyngeal culture, observation and erythromycin prophylaxis the following are vaccine doses are recommended for contacts of cases in some countries with developed economies (e.g., Australia, New Zealand):

• Fully immunised children up to 5-7 years of age - 1 dose of DT
• Fully immunised children over 5-7 years - 1 dose of Td
• Unimmunised children up to 5-7 years - 1-3 doses of DT or child sized diphtheria dose-containing combination vaccine as appropriate at monthly intervals to catch them up to their local immunisation schedule.
• Unimmunised children aged 5-7 years or older - 3 doses of Td at monthly intervals.
  

Contraindications

Anaphylaxis to a previous dose or any components of the diphtheria-containing vaccine should not be given another dose.
If encephalopathy occurs within 7 days of using a combination vaccine with a pertussis component in it (without any other cause to explain it), then further doses of diphtheria immunisation should be given in the form of DT or Td. If an individual has an evolving neurological condition, DT or Td should be used in preference to pertussis-containing combination vaccines, or if this is not feasible, immunisation delayed until the condition is fully diagnosed or stabilises.

Adverse Reactions

Systemic reactions: usually mild and of short duration. 

Local reactions:  Up to half of children may have pain, redness or swelling at the injection site. Extensive swelling of the limb around the injection site can occasionally occur – this is more likely after the 4th and 5th dose. Diphtheria vaccine is commonly combined with tetanus and pertussis vaccines, so adverse reactions relating to those components can also occur.

Disease	Risk of disease	Risk of vaccine
Diphtheria - a highly contagious respiratory illness causing severe pharyngitis.  Toxigenic strains may cause myocarditis and peripheral neuropathy.	Pharyngitis causing moderate to severe upper airway obstruction in 90% of cases. The most common complications are myocarditis and neurological manifestations . Less common complications include renal failure secondary to tubular necrosis, stupor, coma and death.   Overall case fatality 1% if treatment begins within 1 day of symptom onset and 20% if delayed beyond 4 days.	50% mild local or systemic reactions (self-limiting). Brachial neuritis (from the tetanus component) 0.5-1 in 100,000. Encephalopathy (temporal association with pertussis component) <1 in 1,000,000. Anaphylaxis 1 in 1,600,000.

Description of Diphtheria disease can be found in the Immunisation Handbook 2006.

• Link to Immunisation Handbook (2006)  Chapter 4 - Diphtheria