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Diphtheria

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Introduction

You may be familiar with diphtheria because it is included in your local vaccination schedule, but 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 disease 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 major 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 in conflict areas.

Credit: A ghostly skeleton trying to strangle a sick child; representing diphtheria. Watercolour by R. Cooper.
Wellcome Collection.

Pathophysiology

Diphtheria is caused by the aerobic gram-positive bacterium Corynebacterium diphtheriae. Symptoms are produced by toxigenic C. diphtheriae strains; 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 gives rise 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 due to 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 involve both motor and sensory nerves, and may closely 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 the clinical features (such as the presence of a pseudomembrane). Do not wait until microbiological confirmation which may take days. Early recognition and treatment is essential to prevent complications.

Treatment

As always, prevention is the best treatment: vaccination is very effective against diphtheria. The vaccine is a toxoid vaccine containing an inactivated toxin. There are few side effects of the vaccination, 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 a significant proportion of children need to be admitted to the PICU.

The main therapy is a single dose equine-derived antitoxin that neutralizes circulating toxin and prevents its sequelae. If given promptly it can greatly 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 are 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 come back 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.

About the authors

  • Marijn is a resident in paediatrics at the Sophia Children's Hospital in Rotterdam, the Netherlands. He is interested in infectious diseases, neonatology, and acute medicine. In his free time he likes to play tennis, read books, and worship his two cats.

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