Diphtheria

• Diphtheria is poisoning by a toxin made by some strains of the bacterium Corynebacterium diphtheriae. The bacteria sit in the throat or on skin and release a toxin that enters the blood and shuts down protein synthesis in human cells. ^{[1][10] [7]}
• The famous sign is a tough grey-white pseudomembrane across the tonsils and throat that can block the airway, with fever, sore throat and a swollen "bull neck". ^[1][3]
• The toxin also damages the heart, nerves and kidneys one to several weeks later: myocarditis in days 7 to 14, cranial and limb paralysis weeks to months later, and kidney injury. ^[10]
• Treatment is two things at once: diphtheria antitoxin (DAT) to neutralise circulating toxin, plus an antibiotic (a macrolide such as azithromycin, or penicillin) to kill the bacteria. ^[2][10]
• Prevention is vaccination with diphtheria toxoid: a 3-dose primary series followed by boosters, with total protection rising to about 99% after five doses. ^[8][10]
• Diphtheria is reportable everywhere it occurs. Suspected cases need urgent clinical care and public health notification, because bacteria spread by droplets and fragments of pseudomembrane can obstruct the airway. ^[1][2]

By the end of this page you should be able to:

1. Explain why only some strains of C. diphtheriae cause diphtheria, and how the diphtheria toxin kills cells.
2. Recognise respiratory and cutaneous diphtheria, including the pseudomembrane, "bull neck" and airway risk.
3. List the toxin's effects on the heart, nervous system and kidneys, and when each appears.
4. Plan first-line treatment: which patients need DAT, the dose by presentation, and which antibiotic to choose, with doses from current guidance.
5. Order the right cultures and toxin tests, and explain why confirming toxin production matters.
6. Manage close contacts: quarantine, prophylaxis, vaccination.
7. Give the WHO and CDC childhood vaccination schedules and the adult booster interval.
8. Describe care in low-resource settings and when to refer.

Two things must happen for a strain to cause diphtheria. First, the bacterium must be infected by a bacteriophage carrying the diphtheria tox gene, or come from a strain already carrying it. Second, the tox gene must actually be expressed so that toxin is made. Strains without the gene, or strains that carry it but do not express it, are non-toxigenic; they do not cause diphtheria and diphtheria antitoxin does not help them. ^[1][6]

Two related species can carry the same toxin gene. Toxin-producing Corynebacterium ulcerans, a zoonotic species usually caught from dogs or cats, can cause an illness indistinguishable from respiratory diphtheria and is treated with antitoxin in several countries. Toxin-producing Corynebacterium pseudotuberculosis usually causes lymphadenitis, not classical diphtheria. ^[3][10]

Biochemically, C. diphtheriae is split into four biovars: Gravis, Mitis, Intermedius and Belfanti. These can be separated by glycogen fermentation and nitrate reduction, but in everyday practice the distinction has little bearing on diagnosis or treatment. ^[10]

Clinically, disease is classified by site:

• Respiratory diphtheria: pharyngeal and tonsillar (most common), laryngeal, nasal, or diffuse with neck swelling. ^[3]
• Cutaneous diphtheria: slow-healing ulcers with a clearly demarcated edge and a membrane. ^[3]
• Diphtheria with toxin effects: myocarditis, neuritis, occasionally kidney injury. ^[10]

The bacteria spread person to person, mainly by respiratory droplets, sometimes by direct contact with lesions, rarely on contaminated objects. The incubation period is usually 2 to 5 days, with a range of 1 to 10 days. ^[1]

Diphtheria was a major childhood killer before vaccination. Mass immunisation, which began with toxoid in the 1920s, drove cases down: WHO's expanded immunisation programme reduced annual cases from about one million in the 1970s to fewer than 60,000 after 1983. ^[10]

The disease is now unevenly distributed. Diphtheria is reportable but rare in high-income countries and usually linked to travel or migration in unvaccinated people. In Europe there were 224 reported cases in 2022, compared with an average of 55 per year between 2017 and 2021. WHO reported 27,778 cases worldwide in 2023. ^[10]

Large outbreaks still happen where routine immunisation is disrupted. In 2023-2024 West Africa (Nigeria, Guinea, Niger and neighbours) saw nearly 1,000 deaths among about 18,500 reported cases, of whom only 24% were fully vaccinated. ^[10]

Diphtheria is fatal in 5 to 10% of cases overall, with higher rates in young children. ^[8] An untreated, never-vaccinated person is estimated to die in about 29% of cases, mostly from asphyxia as the airway blocks. ^[10] Children under 5 years and adults over 40 years have the highest death rates, up to 20%. ^[3]

Where diphtheria still occurs, cases rise fastest when vaccination coverage falls. A coverage of 80 to 85% in a population is the level at which epidemic risk clearly falls. ^[10]

Risk is determined almost entirely by immunity and exposure, not by any host gene.

• No immunity: unvaccinated or incompletely vaccinated people, and those whose last dose was long ago; protection wanes with time. ^[8][10]
• Close contact: household members, people with habitual close contact, and anyone directly exposed to secretions from the infection site are at risk, regardless of vaccination status. ^[1]
• Travel or migration from endemic areas. ^[1]
• Socioeconomic disruption: conflict, poor access to routine immunisation, and crowded accommodation, such as asylum seeker settings, all predispose to outbreaks. ^[9][10]

There is no inherited susceptibility of practical importance, and no modifiable lifestyle risk factor. ^[10]

The whole illness follows from one molecule. Strains of C. diphtheriae carrying an active tox gene release diphtheria toxin into the surrounding tissue. The toxin is a 535-amino-acid protein that enters human cells by binding the membrane-anchored precursor of heparin-binding epidermal growth factor. Inside the cell it catalyses the ADP-ribosylation of elongation factor 2, inactivating protein synthesis and causing cell death by apoptosis. ^[10]

This explains the three parts of the disease.

The pseudomembrane. Locally the toxin kills the surface cells of the nose, throat or skin. Dead cells, fibrin and inflammatory debris form the tough grey-white pseudomembrane, and the surrounding tissue swells. In the pharynx this produces the sore throat, difficulty swallowing and, with neck lymph node swelling, the "bull neck". ^[3][10] If the membrane extends into the trachea it can obstruct the airway. ^[3]

Systemic poisoning. Toxin is absorbed into the blood and reaches the heart, nerves and kidneys. Tissues with high blood flow and active protein synthesis are hit hardest. ^[10]

The delay. Because toxin has to be absorbed, distributed and kill cells, the systemic complications appear days to weeks after the throat symptoms, often when the patient seems to be recovering. ^[10]

The toxin is extremely potent, with an estimated lethal dose of about 100 nanograms per kilogram of body weight. ^[10]

On a throat swab, C. diphtheriae looks like a pleomorphic, club-shaped, gram-positive bacillus, and toxigenic strains carry the tox gene on a bacteriophage. Laboratory confirmation of actual toxin production, not just the gene, is what matters for calling the illness diphtheria. ^[1][6]

Respiratory disease has a gradual onset with mild fever, sore throat, difficulty swallowing, malaise, loss of appetite and, if the larynx is involved, hoarseness. ^[3] The hallmark is the pseudomembrane: it appears within 2 to 3 days, over the tonsils, pharynx, larynx or nares, and may extend into the trachea. ^{[3] [10]}

A useful teaching image is the "bull neck": grossly swollen cervical lymph nodes with soft-tissue oedema. The membrane bleeds if removed. Airway obstruction, myocarditis and neuritis are the dangerous complications. ^[1][3]

Cutaneous disease presents as scaling or crusted ulcers with clearly demarcated edges and a membrane, and these lesions heal slowly. Systemic complications are less common than with respiratory disease, but the patient is still infectious and close contacts are still at risk. ^[3][6]

Most severe complications, including death, are attributable to the toxin rather than to the bacteria. ^[3]

Cardiac. Toxic cardiomyopathy appears 7 to 14 days after the first respiratory symptoms in 10 to 25% of patients, and accounts for 20 to 25% of deaths. It presents as heart failure with orthopnoea, oedema and jugular venous distension, with an irregular pulse. Conduction defects and arrhythmias can need specific treatment and, rarely, a temporary pacemaker. Mortality without treatment is about 50% in historical series and about 8% with modern care. ^[10]

Neurological. Neurological complications develop weeks to months after infection in 15 to 25% of untreated cases and account for up to 15% of deaths. Bulbar paralysis is most common and can appear as early as the second day of illness. Peripheral paralysis is less frequent, about 1% of cases, and can appear up to 3 months later. Patients have difficulty swallowing, double or blurred vision, ocular muscle weakness, breathing difficulty from respiratory muscle paralysis, sensory loss or limb weakness. In one series, 20% of patients with neurological complications needed ventilation. ^[10]

Renal. Kidney injury is less well described but real: in one recent series of 32 hospitalised patients with upper-airway diphtheria, 73% had altered renal function with proteinuria in 58% and haematuria in 42%. ^[10]

Respiratory diphtheria can be mistaken for several other infections that give a sore throat and membrane, and other Corynebacterium species can mimic it. ^[3]

For cutaneous diphtheria, consider other ulcerative or membranous skin infections, including skin infections due to group A streptococcus or Staphylococcus aureus. ^[3]

The diagnosis of diphtheria rests on the clinical picture; laboratory tests confirm it and decide public health action. ^[1][6]

• Cultures from the suspected site: nose and throat (or nasopharynx), any mucosal or cutaneous lesion, and, if possible, beneath the membrane or a piece of it. Collect before starting antibiotics, because specimens are more likely to grow the organism beforehand. Standard swabs are adequate. ^[6]
• Identification: C. diphtheriae grows as gram-positive bacilli and is identified by biochemical tests, MALDI-TOF mass spectrometry or PCR. ^[6]
• tox gene detection: PCR for the tox gene, done at some state public health laboratories and at the reference laboratory. ^[6]
• Toxin production (Elek test): an immunoprecipitation assay that proves the strain actually makes toxin. This is the step that confirms diphtheria, because many strains in high-income countries carry but do not express the tox gene. Where toxin production is not confirmed, diphtheria antitoxin is not indicated. ^[6]

Two consecutive negative cultures 24 hours apart, once antibiotic therapy is finished, document elimination of toxigenic bacteria in all presentations. ^[2]

There is no numerical scoring system in current guidance. Severity is assessed clinically and drives two decisions: whether to give DAT and at what dose.

A suspect or confirmed case of respiratory diphtheria is eligible for DAT. ^[5] Cutaneous disease usually does not need antitoxin. ^[2]

WHO's current dosing (same for adults and children) is by presentation and duration: ^[10]

A single dose only is recommended, because repeat dosing risks hypersensitivity reactions. ^[10]

Begin presumptive therapy as soon as diphtheria is suspected clinically, before laboratory confirmation. ^[2] Notify the local or national public health authority at once. ^[2][9]

• Airway: assess continuously; be ready to intubate or perform a surgical airway if the membrane obstructs. ^[2][3]
• Droplet precautions for respiratory disease until the patient finishes antibiotics and is culture-negative; contact precautions for cutaneous disease until culture-negative. ^[2]
• Monitoring: cardiac and neurological, with readiness for heart failure, arrhythmia and respiratory muscle weakness. ^[2][10]

DAT neutralises toxin still circulating in the blood but not toxin already inside cells, which is why giving it early matters: a meta-analysis found it reduces mortality by 76% when given within two to three days of the first symptoms. ^[10]

DAT is given once, preferably intravenously, or intramuscularly in moderate cases, added to an optional test dose depending on the product. The dose is the same for adults and children, by presentation, as in the table above. ^[10]

Unlike older advice, current WHO guidance does not require a skin sensitivity test or routine premedication, though staff and emergency drugs (adrenaline, bronchodilators, antihistamines, corticosteroids, high-flow oxygen) must be available. ^[10]

In the United States, DAT is no longer manufactured and is supplied by CDC as an expanded-access investigational product after consultation with the state health department and a CDC diphtheria duty officer (CDC Emergency Operations Center, 770-488-7100). DAT is licensed only for suspect or confirmed respiratory diphtheria, including disease caused by toxin-producing C. ulcerans. ^[5]

Antibiotics are needed in every case to eradicate carriage, shorten infectiousness and reduce transmission. ^[2][10]

WHO's 2024 guideline recommends a macrolide (azithromycin or erythromycin) as first-line in preference to a penicillin, a strong recommendation acknowledged to rest on low-certainty evidence. ^[2][10] Other regimens:

• For mild disease, such as a small cutaneous lesion with no systemic upset, an oral macrolide (clarithromycin, azithromycin or erythromycin) is preferred. ^[10]
• For severe disease, intravenous benzylpenicillin is combined with a macrolide. ^[10]
• Where the patient is both extremely and systemically unwell, add a third agent such as intravenous vancomycin or linezolid until susceptibility results return. ^[10]

CDC recommends only erythromycin or penicillin for respiratory and cutaneous disease, and notes that high rates of penicillin resistance are reported in several regions. ^[2] Therefore obtain local susceptibility testing during outbreaks and tailor treatment. ^[10]

With antibiotics, respiratory colonisation clears in about 5 days on average, shortening infectivity by up to two weeks. ^[10]

• Cardiac care: treat heart failure, arrhythmia and conduction defects; insert a temporary pacemaker if required. ^[10]
• Respiratory support for laryngeal or neurological involvement, including ventilation. ^[3][10]
• Treatment of secondary pneumonia, and general supportive care.

Every suspected case is investigated by the local health authority to identify close contacts. ^[2][9] Management of close contacts includes: ^[2]

• Quarantine for 7 to 10 days after last exposure, with monitoring for diphtheria.
• Cultures from nose and throat.
• Prophylaxis with erythromycin or penicillin. Where compliance is a concern, give a single intramuscular dose of benzathine penicillin.
• Vaccination for anyone not up to date, with an extra dose for anyone whose last diphtheria-containing vaccine was more than 5 years ago.

UKHSA's 2025 guidelines for England (GOV-19100) set out the same framework of investigation and control of cases and close contacts; the PDF runs to 66 pages and includes supplementary guidance for asylum-seeker accommodation settings. ^[9]

Diphtheria may not confer lasting immunity, so all recovering patients should be brought up to date with diphtheria-containing vaccine during convalescence. ^[2]

Document eradication of toxigenic organisms with two consecutive negative cultures 24 hours apart after antibiotics are completed, before releasing droplet precautions. ^[2]

• Airway obstruction from the pseudomembrane, including life-threatening laryngeal disease. ^[3]
• Myocarditis and arrhythmia, days 7 to 14; up to 20-25% of deaths. ^[10]
• Neuropathy: bulbar palsy and limb paralysis weeks to months later, with possible respiratory muscle involvement. ^[10]
• Kidney injury. ^[10]
• Death from asphyxia or toxin effects. ^[10]

With early antitoxin and antibiotics, mortality is much lower than the historical untreated figure of about 29%. ^[10] Where treatment is late, deaths come from myocarditis (20-25% of deaths) and neuropathy (up to 15%). ^[10] Neurological survivors in one series still had limb symptoms a year later and 6% could not walk independently. ^[10]

Diphtheria vaccine is a toxoid: toxin inactivated by formalin, given alone or combined with tetanus and pertussis (DTaP/DTwP, pentavalent), or with tetanus only in lower concentration (Td) for older age groups. ^[8][10] Efficacy is about 94% after three doses and 99% after five; three doses are estimated 87% effective against symptomatic disease and to reduce transmission by 60%. ^[10] Vaccination alone interrupts transmission in only 28% of outbreak settings, so antibiotics and isolation remain essential. ^[10]

WHO recommends a 3-dose primary series starting as early as 6 weeks of age, with at least 4 weeks between doses, followed by 3 booster doses, preferably at 12-23 months, 4-7 years and 9-15 years, with at least 4 years between boosters. ^[8]

CDC (United States) schedule: ^[4]

• DTaP, 5 doses for children under 7 years: at 2, 4 and 6 months, 15 to 18 months, and 4 to 6 years.
• Tdap, 1 dose at 11 to 12 years.
• Adults: diphtheria-containing vaccine every 10 years, using Td or Tdap after the first Tdap dose.
• DT vaccine is no longer available in the United States; children under 7 years receive DTaP.

UK practice follows the national NHS schedule administered within the UKHSA's control framework. ^[9]

See close-contact management above. Antitoxin is given to patients, not to contacts: prophylactic equine antitoxin in contacts has no proven benefit beyond vaccine plus antibiotics. ^[3]

Where coverage is poor, outbreaks are controlled by case finding, isolation, antibiotics, contact prophylaxis and catch-up vaccination. The 2023-2024 West African outbreak showed how quickly cases accumulate and how essential DAT procurement is when supplies are scarce: the number of eDAT manufacturers fell from nine in 2016 to six in 2019, and shortages were a bottleneck. ^[10]

• Pregnancy: no specific restriction arises from the toxoid vaccine; follow the standard immunisation schedule for pregnant women in the relevant jurisdiction (for example Tdap in the third trimester in many programmes). Vaccination decisions in pregnancy are routine and safe. (No specific diphtheria guidance differs in the sources used here beyond the general schedule.) ^[4][8]
• Children: the same disease but higher case-fatality under 5 years; immunise from 6 weeks of age. ^[8][3]
• Older adults: booster doses every 10 years; case-fatality rises after age 40. ^[3][4]
• Immunocompromised hosts and HIV infection: diphtheria vaccination is given per the standard schedule; response may be suboptimal, but no special contraindication exists in the sources. ^[4][8]
• Asylum seekers and displaced populations: crowded living and low prior coverage make outbreaks likely; UKHSA has dedicated supplementary guidance. ^[9]

• Suspect diphtheria from the clinical picture; a membrane plus bull neck in a child with low vaccination is enough to treat while arranging confirmation. ^[1][3]
• Culture and Elek testing may be unavailable; send swabs to the nearest reference laboratory and treat on clinical grounds. ^[6]
• Antitoxin may be scarce or absent. WHO's guidance states that where antitoxin is unavailable and unlikely to be accessible soon, there is a speculative benefit to dual antibiotic treatment, and clinicians may treat with both a macrolide and a beta-lactam while awaiting susceptibility results. ^[10]
• Keep droplet and contact precautions simple: isolate the case, mark the bed, and ensure ventilation. ^[2]
• Immunise contacts and catch up whole communities during the response. ^[2][8]

• Diphtheria is toxin poisoning by toxigenic C. diphtheriae, not bacterial invasion. ^[1][10]
• A bacteriophage carrying the tox gene and its expression are both required. ^[1]
• The hallmark is a tough pseudomembrane 2 to 3 days into illness, with fever, sore throat, bull neck and airway risk. ^[3]
• Systemic toxin effects appear late: myocarditis days 7 to 14, neurological complications weeks to months, kidney injury. ^[10]
• Treat every suspected case promptly with both DAT and antibiotics, with droplet and cardiac/neurological monitoring. ^[2][10]
• WHO recommends a macrolide (azithromycin, erythromycin) first line in 2024; CDC lists erythromycin or penicillin; combine a macrolide with intravenous benzylpenicillin in severe disease, and add vancomycin or linezolid in the very sick. ^[2][10]
• DAT dose is by presentation: 20,000 IU for cutaneous or pharyngeal disease of about 2 days, 40,000 IU for nasopharyngeal disease under 48 hours, 80,000 IU for disease over 48 hours or diffuse neck swelling or severe disease; single dose only. ^[10]
• Confirm a toxigenic isolate with toxin production testing (Elek), not just PCR for the tox gene. ^[6]
• Close contacts: 7 to 10 days quarantine, cultures, macrolide or penicillin prophylaxis, benzathine penicillin when compliance is a problem, and catch-up vaccination. ^[2]
• Vaccine: WHO 3 primary doses from 6 weeks plus 3 boosters; CDC DTaP 5 doses, Tdap at 11-12 years, adult booster every 10 years; efficacy about 99% after five doses. ^[4][8][10]
• Outbreaks still kill where coverage slips: 2023-2024 West Africa saw about 1,000 deaths among 18,500 cases. ^[10]
• Antitoxin does not treat infection and no antitoxin in contacts; the cure of disease is antibiotics plus DAT, and the cure of spread is contact prophylaxis plus vaccination. ^[2][10]

Plain text only: see related pages on pharyngitis and tonsillitis, bacterial skin infections, myocarditis, peripheral neuropathy, vaccines in pregnancy, infection prevention and control.