Diphtheria

Diphtheria is a severe, toxin mediated infection caused by Corynebacterium diphtheriae. It is transmitted via respiratory droplets or direct contact.

It is characterised by a thick, adherent grey-white pseudomembrane over the pharyngeal, tonsillar, laryngeal or, less commonly, nasal mucosa. The bacterial exotoxin also has potentially severe, life threatening systemic effects, principally cardiac (myocarditis) and neurological (peripheral neuropathy) toxicity.

It is now rare in populations with high routine childhood vaccination coverage, given the highly effective, long established diphtheria toxoid vaccine. It remains an important consideration in unvaccinated or under-vaccinated individuals and in regions with lower vaccination coverage.

Recent outbreaks in several regions reflect declining vaccination coverage. Awareness remains important for this uncommon, potentially severe and entirely vaccine preventable condition.

Pathophysiology

• Strains of Corynebacterium diphtheriae carrying the bacteriophage that encodes the diphtheria toxin gene produce a potent exotoxin. The exotoxin inhibits protein synthesis within host cells through inactivation of elongation factor 2.
• Local toxin effects at the site of mucosal infection produce the characteristic tissue necrosis and inflammatory exudate that forms the pathognomonic pseudomembrane.
• Systemic absorption and distribution of the toxin produces potentially severe, life threatening distant organ toxicity. It particularly affects the myocardium (myocarditis, the leading cause of death in this condition) and peripheral nerves (a characteristic, often delayed onset peripheral neuropathy).
• The pseudomembrane is firmly adherent to the underlying mucosa. Attempted removal typically causes bleeding from the denuded mucosal surface. This reflects the direct, local necrotising effect of the toxin and is a useful clinical distinguishing feature from the more loosely adherent, readily removable exudate typical of other causes of pharyngitis or tonsillitis.
• Non-toxigenic strains of Corynebacterium diphtheriae lack the toxin encoding bacteriophage. They can still cause localised infection but not the severe systemic toxin mediated complications of toxigenic strains. This microbiological distinction has direct relevance to disease severity and management.

• Pharyngeal or tonsillar diphtheria presents with sore throat, low grade fever, and malaise. The characteristic finding is a thick, adherent, grey-white pseudomembrane extending across the tonsils and pharynx.
• In more severe cases, significant cervical lymphadenopathy and soft tissue swelling produce a characteristic "bull neck" appearance, reflecting substantial local tissue oedema and inflammation.
• Laryngeal diphtheria, either primary or extending from pharyngeal disease, presents with hoarseness, a characteristic barking cough, and progressive stridor. It carries particular risk of critical airway obstruction, because the pseudomembrane and mucosal swelling can compromise the relatively narrow laryngeal airway.
• Systemic toxin mediated complications develop over the course of the illness, sometimes with a delayed onset relative to the initial local infection.
• Myocarditis presents with arrhythmia, heart failure, or, in severe cases, cardiogenic shock. It typically develops within the first one to two weeks of illness and is the leading cause of diphtheria related mortality.
• Peripheral neuropathy characteristically has a delayed onset, sometimes several weeks after the initial illness. Palatal and pharyngeal weakness is often an early feature, followed by a more generalised, symmetric peripheral neuropathy. In severe cases this produces significant respiratory muscle weakness requiring ventilatory support.
• Cutaneous diphtheria presents with a chronic, non-healing ulcer with a similar grey-white membrane. It is a less common presentation, particularly relevant in specific tropical and resource limited settings. It is generally associated with less severe systemic toxin effects than respiratory tract disease, given more limited local toxin production and absorption at this site.

• Diagnosis is initially clinical. It rests on a firmly adherent, grey-white pseudomembrane in a patient with a compatible presentation and relevant epidemiological context: unvaccinated or under-vaccinated status, or travel or contact history to a region with ongoing diphtheria transmission.
• Start treatment promptly on clinical suspicion, without waiting for microbiological confirmation, given the time-critical nature of specific antitoxin treatment.
• Throat swab or, where present, membrane swab culture on selective media, with polymerase chain reaction testing where available, provides microbiological confirmation of Corynebacterium diphtheriae.
• Test for toxin production, using either the classical Elek test or molecular detection of the toxin gene. This is essential to confirm toxigenic strain infection and to inform severity assessment and prognosis.
• Cardiac assessment includes electrocardiography because of the risk of myocarditis. Where indicated by clinical findings or electrocardiographic abnormality, add cardiac biomarker testing and echocardiography.
• Perform ongoing serial clinical and, where indicated, formal neurological assessment given the risk of delayed onset peripheral neuropathy.
• Both forms of systemic toxin mediated complication can have a delayed onset relative to the initial presentation. They require proactive, structured surveillance throughout the illness course.

• Diphtheria antitoxin, derived from hyperimmune equine serum, is the essential, specific treatment. It neutralises circulating, unbound toxin. Give it promptly on clinical suspicion, without waiting for microbiological confirmation.
• Antitoxin can only neutralise toxin that has not yet bound to host tissue, so any delay directly and substantially worsens the anticipated severity of systemic toxin mediated complications.
• Dose according to the extent and severity of local disease and the duration of illness at presentation. Take appropriate precautions and monitor for hypersensitivity reaction, given the equine origin of the product.
• Antibiotic therapy, with either procaine penicillin or erythromycin as standard options, eradicates the organism, halts ongoing toxin production and reduces the risk of onward transmission to close contacts. Antibiotics alone, without antitoxin, cannot address toxin already produced and circulating.
• Airway management is essential, with a low threshold for early, controlled intubation or, where required, tracheostomy. The risk of progressive, potentially critical airway obstruction from the pseudomembrane and mucosal swelling is particularly relevant for laryngeal diphtheria.
• Approach airway instrumentation and any manipulation of the pseudomembrane with particular caution, given the risk of precipitating bleeding or dislodging membrane material with further airway compromise.
• Provide close, full cardiac monitoring throughout the illness because of the risk of myocarditis. Manage any cardiac complications with standard heart failure and arrhythmia principles.
• Give full supportive care and, where peripheral neuropathy causes significant respiratory muscle weakness, ventilatory support.
• Apply strict isolation precautions. Identify and manage close contacts promptly, with antibiotic prophylaxis and assessment of vaccination status. Give vaccination or a booster dose to any contact with incomplete or uncertain immunisation status.
• Notification to public health authorities is mandatory, given the public health implications and outbreak potential of this condition.
• Prevention is the single most effective public health measure. Maintain high routine childhood vaccination coverage with the diphtheria toxoid containing combination vaccine, with booster doses according to the standard national immunisation schedule.
• Recent outbreaks in regions with declining vaccination coverage underscore the need for robust, full vaccination programmes.