Introduction
You may be familiar with diphtheria because it is included in your local vaccination schedule. Still, the chances that you have encountered a child suffering from the disease are considerably slimmer. Diphtheria has been around for centuries: Hippocrates may have described it 2500 years ago when he wrote about an influenza-like illness causing skin lesions and “arachnoid” formations in the mouth. French physician, Pierre Bretoneau, named the disease diphtheria in 1826 after the Greek word diphthera (leather). This referred to the tough pseudomembranes that form in the patient’s throat. Diphtheria was a significant cause of childhood death but is now very rare in high-income countries thanks to vaccination. There continue to be small-scale outbreaks, such as recently in Australia. It is also more common in regions with poor vaccination rates, such as the former Soviet Union, and conflict areas.
Wellcome Collection.
Pathophysiology
Diphtheria is caused by the aerobic gram-positive bacterium Corynebacterium diphtheriae. Toxigenic C. diphtheriae strains produce symptoms; a toxin is only present if a bacteriophage introduces the toxin gene (tox gene) into the bacterium. Humans are the only known reservoir for C. diphtheriae. Commensal carriage is possible, but the absence of a tox gene does not necessarily mean that these bacteria won’t acquire the gene in the future.
C. diphtheriae infects mucous surfaces, usually the pharynx and tonsils in the respiratory tract and the skin. The incubation period is around 2-4 days. Transmission occurs via respiratory droplets or by direct exposure to skin lesions. After infection, the toxin leads to local tissue necrosis and a strong inflammatory response. This may give rise to a grey-brown, leather-like pseudomembrane. Locally, this causes immobilisation of the pharynx and other tissues. The circulating toxin can produce nerve damage (demyelination), cardiomyopathy, and kidney damage (tubular necrosis).
Another species of the same genus, Corynebacterium ulcerans, is carried by several animal species and can cause a similar disease in humans.
Symptoms and complications
Respiratory and cutaneous symptoms are common in diphtheria:
A sore throat is most often the presenting symptom with pseudomembrane formation on the tonsils, uvula or palate. They have also been described in the lung. There may also be swelling of lymph nodes in the neck, giving a “bull-neck” appearance. Rarely, this oedema can lead to airway compromise due to lymph node swelling, local paralysis due to toxin production, or the presence or dislocation of a pseudomembrane.
Fever is relatively uncommon (it occurs in less than half of the patients); so are dysphagia, malaise, and headache.
Cutaneous symptoms include grey-brown non-healing ulcers on the skin, most often on the extremities. These are painful and tender and may produce an exudate. Cutaneous symptoms are becoming more common. This change in symptomatology may be explained by more adults with lower antibody levels suffering from the disease than in the past, but the pathophysiological reason is unknown. Occasionally the lesions may affect the ears, eyes, or genital tract.
In addition to airway and mucosal symptoms, the following complications can occur:
Cardiac involvement is most common after respiratory involvement. It is due to the direct effects of the toxin. A higher-than-expected pulse rate (based on body temperature) is often an early sign. Dysrhythmias (heart blocks, AV dissociation, ventricular tachycardias), myocarditis, and heart failure can occur. Cardiomyopathy is the greatest cause of death in diphtheria. Endocarditis may occur but is uncommon; it is much more likely if there has been cutaneous involvement.
Neuropathy may begin with local paralysis of the pharynx or palate, then later cranial neuropathy damaging facial, pharyngeal, or laryngeal nerves. This leads to a risk of aspiration. Respiratory muscles then become involved leading to respiratory failure. Peripheral nerve damage is often due to demyelination and occurs later in the clinical course. It can affect both motor and sensory nerves and may resemble Guillain-Barré syndrome. If patients survive, complete recovery is possible.
Disseminated intravascular coagulation and renal involvement (tubule necrosis) have been commonly described.
Arthritis is uncommon but can be caused by strains not carrying the tox gene
The mortality rate is around 5-10%. It can be much higher (around 20%) in children under five years old and the elderly.
Diagnosis
Diagnosis is usually made by culturing swabs from the oropharynx and (if applicable) cutaneous lesions. The microbiological laboratory should be notified if diphtheria is suspected, as specific culture mediums are needed. The presence of the toxin can be proven with a modified Elek agar immunoprecipitation technique, but this testing is not available in all laboratories. Polymerase chain reaction (PCR) is used to identify the bacterial species and/or confirm the presence of the tox gene.
Treatment should be commenced when diphtheria is suspected based on clinical features (such as the presence of a pseudomembrane). Do not wait until microbiological confirmation, which may take days. Early recognition and treatment are essential to prevent complications.
Treatment
Prevention is the best treatment: vaccination is very effective against diphtheria. The vaccine is a toxoid vaccine containing an inactivated toxin. The vaccination has few side effects, and it is usually given as part of a combination vaccine. It is important to know that vaccination does not decrease the carriage of C. diphtheriae.
Treatment should be given in specialised centres, and many children need to be admitted to the PICU.
The main therapy is a single dose equine-derived antitoxin that neutralises circulating toxin and prevents its sequelae. If given promptly, it can significantly reduce mortality. Some patients can be hypersensitive to equine-derived antitoxins. The antitoxin may have no effect if there is only cutaneous involvement.
Antibiotics are also needed. They decrease toxin production and prevent transmission. They also can eradicate the carriage of the bacterium. A course of erythromycin or penicillin is recommended and is usually started intravenously and given for 14 days.
Further treatment is generally supportive. Respiratory tract obstruction may require intubation and mechanical ventilation. Sometimes, a tracheotomy is performed to preserve the airway.
Patients should be isolated; the United States CDC recommends this until cultures return negative, while other centres recommend shorter periods of isolation.
Antibiotics and booster vaccination can also be used as post-exposure prophylaxis.
Selected References
Byard RW. Diphtheria – ‘the strangling angel’ of children. J Forensic Leg Med 2013;20:65-8.
Hadfield TL et al. The pathology of diphtheria. J Inf Dis 2000;181:S116-20.
Hall E et al. (editors). Center for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. Edition 14. Washington, D.C.: Public Health Foundation, 2021.
Holmes RK. Biology and molecular epidemiology of diphtheria toxin and the tox gene. J Inf Dis 2000;181:S156-67.
Kliegman R (editor). Nelson textbook of pediatrics. Edition 21. Philadelphia, PA: Elsevier, 2020
Mammas IN and Spandidos DA. Paediatric virology in the Hippocratic corpus. Exp Ther Med 2016;12:541-9
The Guardian. Two children diagnosed with first cases of diphtheria of the throat in NSW this century. https://www.theguardian.com/australia-news/2022/jul/03/toddler-diagnosed-with-first-case-of-diphtheria-of-the-throat-in-nsw-in-a-century; accessed on 3 July 2022.
Truelove SA et al. Clinical and epidemiological aspects of diphtheria: a systematic review and pooled analysis. Clin Inf Dis 2020;71:89-97.
