Diphtheria

• The organism is pathogenic only in humans.
• Corynebacterium diphtheriae is a Gram-positive, aerobic, non-motile, rod-shaped bacterium.
• The bacterium is classified as gravis, mitis or intermedius.
• Pharyngeal or cutaneous diphtheria is caused by toxigenic strains of C. diphtheriae and occasionally by C. ulcerans. The latter is usually an infection of cattle.
• A fibrinous pseudomembrane is produced usually on the respiratory mucosa.
• An exotoxin affects a number of tissues including the heart, peripheral nerves, and kidneys.

• It mainly occurs in epidemics.
• A vaccine was introduced to the UK in 1941, after which the number of cases fell from 46,281 (2,480 deaths) in 1940, to 37 cases (6 deaths) in 1957.²
• From 1986 to 1995 38 isolates of toxigenic C. diphtheriae were identified by the PHLS Diphtheria Reference Unit. Of these, 19 were carriers and 7 were cutaneous infections. Since then it has almost disappeared with sporadic cases imported from abroad by non-immune people.³
• Tests on blood donors suggest that many adults are susceptible. This is not a problem when there is no reservoir of the disease, but they are potentially at risk if they visit endemic areas.
• Diphtheria persists in developing countries and there was a resurgence in parts of the former Soviet Union because of a break down in the vaccination programme.⁴ The resurgence started in 1991 and in 1995 there were around 52,000 cases and 1,700 deaths.²
• On a global scale there were 8,229 cases reported to the WHO in 2005 and an estimated 5,000 deaths in 2002.⁵
• Not all Corynebacteria are toxigenic and unless the patient has recently returned from an endemic area, it is appropriate to withhold control measures until identification has been positive.⁶
• Figures for statutory notifications have to be interpreted with caution as they include non-toxigenic strains. There may also be under-reporting.⁷

• Spread is via respiratory droplets or contact with exudate from skin lesions.
• Once recovered some patients become carriers for weeks, months or even a lifetime.
• Cutaneous diphtheria is most often associated with the homeless and those with poor personal and community hygiene.
• Poor living conditions and lack of immunisation, especially where there is not an immunization programme, increase risk.
• Adults are at risk as they lose protection from childhood vaccines unless they have boosters. 70% of older adults are at risk.

Incubation period

It is usually 2 to 5 days, but may be up to 10 days.⁶

Presentation

• Very early symptoms may be similar to the common cold. Often it presents with a nasal discharge that is initially watery and becomes purulent and blood-stained. The nostril can be sore or crusted with the pseudomembrane sometimes visible within the nostril.
• In diphtheria of the upper respiratory tract, there is a membranous pharyngitis (often referred to as a pseudo-membrane) with fever, enlarged anterior cervical lymph nodes and oedema of soft tissues giving a "bull neck" appearance.
• The pseudo-membrane may cause respiratory obstruction.
• Swallowing may be made difficult by unilateral or bilateral paralysis of the muscles of the palate.
• The exotoxin also affects other parts of the body, including the heart and nervous systems. It may cause paralysis and cardiac failure.
• Milder infections resemble streptococcal pharyngitis and the pseudo-membrane may not develop, particularly where they has been previous vaccination.
• Asymptomatic carriage is possible and an important source of transmission.
• Cutaneous infection is usually mild, but chronic:
  • Typical findings are vesicles or pustules that quickly rupture to form a "punched-out" ulcer up to several centimetres in diameter.
  • It often appears on the lower legs, feet and hands.
  • It may be painful in the first week or two and covered with a dark pseudomembrane which separates to show a haemorrhagic base which may have exudate.
  • The surrounding tissue is pink or purple and oedematous.
  • It usually heals in 2 or 3 months to leave a depressed scar.
• Infections at other mucocutaneous sites include otitis media, conjunctivitis and vulvovaginitis.
• Sporadic cases of septic arthritis occur.

Effects of toxin

• Cardiomyopathy and myocarditis is usually evident by the 10 to 14th day. There may be arrhythmias early or late in the illness. Myocardial involvement accounts for around half of all deaths.
• Neuritis affects motor nerves, firstly with paralysis of the soft palate, causing dysphagia and nasal regurgitation, then ocular nerves, peripheral nerves and diaphragm with resulting infection and respiratory failure.
• Nephritis and proteinuria may be features.
• Thrombocytopenia may be seen in the full blood count.

• Infection with C. ulcerans also causes membranous tonsillitis, but is rarely toxic.
• C. pseudodiptheriticum does not produce a toxin, but can cause exudative pharyngitis with a pseudomembrane.
• The disease may also resemble infectious mononucleosis, streptococcal or viral tonsillitis, peritonsillar abscess, oral thrush, epiglottitis, herpes simplex and impetigo.
• If there are neurological symptoms and a lumbar puncture is performed, elevated protein in the CSF may lead to a false diagnosis of Guillain-Barré syndrome.

• Bacterial culture from patient and close contacts
• Toxigenicity tests by specialist laboratories
• Polymerase chain reaction
• Serum AST and ECG in cardiac cases

Non-drug

• Antitoxin should be given within 48 hours of the onset of symptoms, which can be before bacteriological confirmation:
  • Myocarditis and palsies do not respond to corticosteroids or delayed administration of antitoxin.
  • The antitoxin is derived from horse serum and so reactions are common and sensitivity testing is necessary.
  • Dosage is determined by the site of infection, and severity.
  • The HPA document has a table of recommended doses.⁶
• Barrier nursing is required. The disease can be spread by contact with clothing and bed linen.
• Cutaneous lesions should be thoroughly cleaned with soap and water. Antitoxin is of no value for cutaneous diphtheria.²
• Patients should be immunised in the convalescent stage because clinical infection does not always induce adequate levels of antitoxin. They should receive a complete course or a reinforcing dose according to their age and immunisation history as outlined by the HPA.⁶

Drugs

Benzylpenicillin IV is followed by oral penicillin V for 10 to 14 days. Erythromycin is used with penicillin allergy.

Surgical

Urgent tracheostomy may be required for respiratory obstruction.

• Swab all close contacts, treating with antibiotics and confining to home those with positive cultures.
• Contacts need treatment to eliminate both incubating disease and to prevent carriage to others.

The recommended regimen for close contacts is either:⁶

• A single dose of IM benzylpenicillin 600,000 units for children less than 6 years old or 1.2M units for anyone of 6 years or older.
• Or 7 days erythromycin 125 mg every 6 hours for children under 2 years of age, or 250 mg every 6 hours for children aged 2 to 8 years, or 250 or 500 mg every 6 hours for anyone over 8 years of age.

• Paralysis that often involves the muscles of the palate and the hypopharynx is seen in 10 and 20% of patients, beginning as early as the first 10 days of illness.
• Difficulty swallowing and nasal speech are often the first signs of neurological involvement.
• Involvement of other cranial nerves may be delayed until as late as 7 weeks after infection and produce oculomotor paralysis and blurred vision. Diffuse, usually bilateral, motor function deficits resulting from involvement of the anterior horn cells of the spinal cord may be seen as late as 3 months after initial disease, with progression of weakness either from proximal-to-distal regions or, more commonly, from distal-to-proximal regions.
• Diaphragmatic paralysis will result if the phrenic nerve is involved. This may occur at any time between the 1st and 7th weeks of illness.
• Cardiac complications may arise during the first 10 days of the illness or they may be delayed for 2 or 3 weeks by which time pharyngeal disease is subsiding:
  • The first sign of cardiac involvement is tachycardia disproportionate to the degree of fever. Fever is rarely above 39°.
  • Heart block of first, second or third degree may be seen.
  • Atrioventricular dissociation and ventricular tachycardia can develop and congestive heart failure may result.
  • Echocardiogram may demonstrate dilated or hypertrophic cardiomyopathy.
  • In patients who survive, cardiac muscle regeneration and interstitial fibrosis lead to recovery of normal cardiac function, unless toxic damage has led to a permanent arrhythmia.
• Airway obstruction by the diphtheritic membrane and peripharyngeal oedema cause the "strangling" and emergency tracheostomy may be required.

• Overall there is a 5 to10% mortality, but it is up to 20% in those younger than 5 and older than 40 years.
• Recovery is slow and particular caution should be advised after myocarditis.
• Complete recovery from neurological damage is usual in those who survive.

• The Schick test was historically used to test for immunity.
• Vaccination is part of the standard protocol for children, but a booster for adults may be required if going to endemic areas.⁸
• Alternatively at least 1, if not 2 boosters are required for adults and most will achieve life long immunity.⁹
• Uptake of diphtheria vaccine by children of less than 2 years old is 93% and stable.¹⁰
• A few of the remaining 7% may have valid medical reasons for not being immunised, but most are because of parental oversight or misinformation. The WHO target for uptake is 95%.
• Thiomersal, a mercury containing preservative, is present in DTP and DT vaccines. Allegations of a link to neurodevelopmental problems are unfounded.¹¹