Diphtheria is an acute and highly contagious bacterial infection caused by Corynebacterium diphtheriae. It primarily affects the mucous membranes of the upper respiratory tract, including the throat and nose. A characteristic feature of the disease is the formation of a thick, gray or white pseudomembrane, which can obstruct the airway and lead to breathing difficulties.
Transmission occurs through respiratory droplets, direct contact with infected lesions, or contact with contaminated objects. The incubation period typically ranges from 2 to 5 days. Early symptoms include sore throat, low-grade fever, and cervical lymphadenopathy, often resulting in a swollen “bull neck” appearance. In severe cases, the diphtheria toxin can enter the bloodstream, leading to systemic complications such as myocarditis and peripheral neuropathy.
Diphtheria is preventable through vaccination with a diphtheria toxoid, commonly administered as part of combination vaccines such as DTaP (diphtheria, tetanus, and acellular pertussis) or Tdap. Immunity may diminish over time, and booster doses are recommended, particularly for adults and travelers to regions where the disease remains endemic.
Widespread immunization programs have significantly reduced the incidence of diphtheria in high-income countries. However, outbreaks continue to occur in areas with low vaccination coverage, conflict zones, and among displaced populations. Management of diphtheria includes prompt administration of diphtheria antitoxin and antibiotics, typically erythromycin or penicillin. Early detection and treatment are essential to reduce morbidity and mortality rates.
Despite a global decline in cases, diphtheria remains a public health concern in parts of Asia, Africa, and Eastern Europe. Ongoing surveillance, public health education, and access to vaccination are critical in preventing resurgence.
Causative Organism
Diphtheria is caused by the bacterium Corynebacterium diphtheriae. This Gram-positive, non-motile, rod-shaped, aerobic bacterium produces a potent exotoxin that is responsible for the disease’s severe clinical manifestations. Only toxigenic strains—those infected by a specific lysogenic bacteriophage carrying the tox gene—are capable of causing diphtheria in humans.
The diphtheria toxin is classified as an A-B type exotoxin, where the A subunit enzymatically inactivates elongation factor-2 (EF-2), halting protein synthesis and leading to cellular necrosis. This mechanism underlies the formation of the characteristic pseudomembrane seen in respiratory diphtheria.
Laboratory diagnosis involves culturing the bacterium from throat swabs using selective media such as Löffler’s or Tinsdale agar. Confirmation of toxigenicity is performed via the Elek immunodiffusion test, PCR detection of the tox gene, or enzyme immunoassays. In many countries, reference laboratories are designated to perform these confirmatory tests due to the public health implications.
Genomic studies have identified four major biovars of C. diphtheriae: gravis, mitis, intermedius, and belfanti—with the gravis biovar historically associated with more severe epidemics, such as the large-scale outbreak in the former Soviet Union in the 1990s.
Vaccination efforts are directed against the diphtheria toxin itself, using a formalin-inactivated toxoid. As a result, individuals may still carry non-toxigenic C. diphtheriae asymptomatically even after immunization.
In 2023, Nigeria faced a resurgence of diphtheria, with over 6,000 suspected cases and more than 400 confirmed deaths, mainly in under-immunized communities. The outbreak was most severe in Kano and Lagos states, where healthcare access and routine immunization coverage were low.
Historical Significance
Diphtheria was once a leading cause of illness and death worldwide, particularly among children, during the 19th and early 20th centuries. In the United States, annual cases peaked at over 200,000 in the early 1920s, resulting in approximately 10,000 to 15,500 deaths per year (a case fatality ratio around 7–8%). Hospital mortality rates in earlier eras could reach as high as 50%, and a meta‑analysis estimates a case fatality rate of about 29% for untreated, never‑vaccinated individuals—often due to asphyxia.
The late 19th century saw the introduction of serum therapy: Kitasato Shibasaburō and Emil von Behring developed the diphtheria antitoxin in the 1890s, which reduced mortality to 1–5% in treated patients. Behring’s work earned him the first Nobel Prize in Physiology or Medicine in 1901.
The development of the diphtheria toxoid vaccine in the early 1920s (notably by Gaston Ramon) led to rapid adoption of immunization campaigns. For example, diphtheria mortality in Ontario dropped from 10 per 100,000 in 1923 to 1 per 100,000 by 1933. The WHO’s Expanded Programme on Immunization (established 1974) further accelerated decline: global annual diphtheria cases fell from roughly 70,000–90,000 in the 1970s to under 60,000 by the early 1980s.
A major resurgence occurred after the collapse of the Soviet Union: between 1990 and 1995, there were over 150,000 reported cases and about 5,000 deaths across the Commonwealth of Independent States, primarily associated with widespread drops in vaccination coverage.
Since the widespread adoption of vaccines, diphtheria has become increasingly rare in high-income countries, with only a handful of cases annually in the UK and US after the mid‑20th century
Transmission and Epidemiology
Diphtheria spreads primarily through close contact and respiratory droplets. Its occurrence varies significantly worldwide, influenced by vaccination coverage and living conditions. Certain groups face higher risks due to environmental and social factors.
Modes of Transmission
Diphtheria primarily spreads via respiratory droplets when infected individuals cough or sneeze. Transmission risk is highest with close and prolonged contact, particularly in crowded or poorly ventilated settings. In temperate regions, cases typically peak in winter and spring.
The bacterium may also be transmitted through direct contact with infected skin lesions, or via fomites—contaminated objects such as towels or clothing—though such routes are less commonly documented.
Asymptomatic carriage of Corynebacterium diphtheriae is an important driver of transmission, especially in partially immunized or vaccinated populations. In one outbreak in South Africa from January 2024 to May 2025, nearly 50 carrier cases of toxigenic C. diphtheriae were identified during contact tracing among 55 confirmed respiratory cases, indicating a carrier rate of nearly 45% among traced contacts.
Humans are the only known reservoir for toxigenic C. diphtheriae; cases of animal-to-human transmission (e.g., C. ulcerans) are rare and unrelated to respiratory transmission dynamics.
While transmission via contaminated food or water has been occasionally reported historically – such as through raw milk – it is considered exceptional compared to respiratory and direct-contact routes
Global Prevalence
Diphtheria cases have declined sharply in high‑income countries due to widespread vaccination. In 2023, about 84 % of children globally received the three recommended doses of diphtheria-containing vaccine, leaving 16 % under‑ or un‑immunized. Nevertheless, reported cases remain highest in regions with limited vaccine access or disrupted healthcare—such as parts of Asia, Africa, and Eastern Europe.
Global case counts rose sharply in 2023, with nearly 25,000 cases reported worldwide, a threefold increase from 2021; Africa accounted for the majority, driven largely by outbreaks in Nigeria. In Europe, the ECDC reported 281 confirmed diphtheria cases between January 2022 and August 2023—significantly higher than earlier years—primarily in migrant-related settings, including Germany, Belgium, and Czechia.
Risk Factors
- Immunization status: Unvaccinated or incompletely vaccinated individuals face the highest risk. A 2000 case–control study found that lack of vaccination increased diphtheria risk by nearly 19-fold.
- Living conditions: Poor sanitation, overcrowding, and malnutrition—common in urban slums and refugee camps—increase susceptibility
- Age and waning immunity: Children under 15 are most vulnerable, but adults are also at risk when immunity decreases. In the US, coverage for booster vaccines among adolescents is around 90 %, but only about 44 % of adults receive a Tdap booster within 10 years of the last dose.
- Exposure: Close contacts of infected individuals—such as household members and healthcare workers—are at increased risk.
Clinical Manifestations
Diphtheria primarily affects the respiratory tract but can also involve the skin. The disease presents with distinctive symptoms depending on the site of infection. Serious systemic complications may follow due to toxin absorption.
Upper Respiratory Symptoms
The hallmark of respiratory diphtheria is the formation of a thick, gray pseudomembrane on the tonsils, pharynx, or nasal cavity. This membrane can cause airway obstruction and bleeding if removed. Initially, patients experience sore throat, mild fever, and malaise.
As the infection advances, neck swelling known as “bull neck” occurs due to cervical lymphadenopathy and soft tissue edema. Difficulty breathing, hoarseness, and cough are common. Respiratory distress may develop quickly, requiring urgent intervention.
Cutaneous Diphtheria
Cutaneous diphtheria manifests as non-healing skin ulcers covered by a gray membrane. Lesions often arise on exposed areas such as the legs or arms, usually following minor trauma or insect bites. The ulcer base may be inflamed.
This form is generally less severe systemically but can serve as a reservoir for infection transmission. Healing tends to occur slowly, with potential scarring. Secondary bacterial infections can complicate the presentation.
Complications
The diphtheria toxin can cause severe systemic effects by inhibiting protein synthesis in distant organs.
- Myocarditis is a frequent and serious complication, occurring in approximately 10–25 % of respiratory diphtheria cases. It typically emerges days to weeks after symptom onset and may lead to arrhythmias, conduction blocks, and heart failure. Historically, myocarditis carried a fatality rate of up to 60 %, though outcomes vary, with mortality now ranging from 14 % to over 60 % depending on severity and care.
- Neurological complications affect between 15–27 % of diphtheria patients. These include peripheral neuropathy and cranial nerve palsies, such as palatal paralysis, which often leads to swallowing difficulties. Onset typically occurs 3 to 5 weeks after initial illness. Clinical case series from India report neurological sequelae in 20–38 % of hospitalized children, with conditions like bulbar palsy, limb weakness, and ventilation-dependent respiratory failure. A 2022 study found bulbar palsy in 57 %, limb weakness in 43 %, and respiratory failure requiring ventilation in 8.6 % of affected children. Recovery ranges from several weeks to months.
- Respiratory failure can result from airway obstruction due to the pseudomembrane or paralysis of respiratory muscles. It is a major contributor to morbidity and mortality, especially when combined with myocarditis or severe neuropathy.
Early administration of diphtheria antitoxin is critical; delays, especially beyond 48 hours after symptom onset are strongly associated with increased risk of severe complications.
Diagnosis of Diphtheria
Diagnosis relies on identifying hallmark symptoms and confirming the presence of Corynebacterium diphtheriae through laboratory methods. Early detection is critical for treatment and preventing transmission.
Clinical Examination
The clinician observes a thick, grayish pseudomembrane on the tonsils, pharynx, or nasal cavity, which is often tightly adherent and bleeds when scraped. Swelling of the neck, called “bull neck,” is frequently present due to cervical lymphadenopathy and soft tissue edema.
Respiratory obstruction signs, such as stridor and difficulty breathing, require urgent attention. A low-grade fever and malaise may accompany the local findings. A detailed history of exposure or vaccination status supports clinical suspicion.
In endemic regions or during outbreaks, clinical diagnosis alone may prompt immediate treatment prior to laboratory confirmation. For example, during the 2017 diphtheria outbreak in Bangladesh among Rohingya refugees, WHO recommended presumptive treatment based on clinical signs to avoid delays in care.
Laboratory Testing
Definitive diagnosis involves culture of a swab from the pseudomembrane or throat. Special media such as Loeffler’s serum medium or potassium tellurite agar (e.g., Tinsdale agar) enhance the growth of C. diphtheriae and allow for preliminary identification based on colony morphology, typically black or gray colonies with a halo on tellurite media.
Identification is confirmed through Gram staining (showing gram-positive, club-shaped bacilli arranged in palisades) and biochemical testing such as nitrate reduction and urease activity.
Polymerase chain reaction (PCR) assays detect the tox gene encoding the diphtheria toxin with high sensitivity and specificity, often yielding results within hours. The presence of the tox gene alone does not confirm toxigenicity; therefore, a toxigenicity test such as the Elek immunodiffusion test is required to demonstrate active toxin production.
Other modern methods, including real-time PCR and MALDI-TOF mass spectrometry, are being evaluated or adopted in high-resource settings for faster turnaround times.
Blood and Ancillary Tests
Routine blood tests are nonspecific. Leukocytosis with neutrophilia may be present. In severe cases, evidence of organ involvement, such as elevated cardiac enzymes, may suggest complications like myocarditis.
Chest radiographs may be indicated to evaluate airway narrowing or pneumonia in patients with respiratory distress.
Treatment
Effective treatment for diphtheria focuses on neutralizing the toxin, eradicating the bacterial infection, and managing symptoms to prevent complications. Each step is critical to reducing mortality and long-term damage.
Antitoxin Therapy
Antitoxin therapy is the primary treatment to neutralize diphtheria toxin circulating in the body. It involves administering diphtheria antitoxin derived from equine (horse) serum. This treatment does not reverse existing tissue damage but halts progression by inactivating unbound toxin molecules.
Early administration is critical, ideally within the first 48 hours of symptom onset. Due to the risk of rapid deterioration, the World Health Organization (WHO) and CDC recommend initiating antitoxin treatment based on clinical suspicion rather than waiting for laboratory confirmation.
- Dosage varies by clinical severity and site of infection. For example:
- Mild pharyngeal or nasal diphtheria: 20,000–40,000 IU
- Moderate disease: 40,000–60,000 IU
- Severe or extensive disease: 80,000–100,000 IU
Skin sensitivity testing is performed prior to administration due to the risk of hypersensitivity to horse serum. Hypersensitivity reactions, such as anaphylaxis and serum sickness, occur in approximately 5–20% of treated patients. Premedication with antihistamines or corticosteroids may be used in high-risk cases.
Antibiotic Management
Antibiotics eliminate Corynebacterium diphtheriae and reduce transmissibility. The two main antibiotics used are:
- Penicillin G: 250,000 to 500,000 units/kg/day IV or IM, divided every 6 hours (max 12–24 million units/day in adults)
- Erythromycin: 40–50 mg/kg/day orally or IV, divided every 6 hours
Duration of treatment is typically 14 days, followed by two consecutive negative throat cultures (taken ≥24 hours apart and at least 24 hours after antibiotic completion) to confirm bacterial clearance.
Erythromycin is the preferred alternative in penicillin-allergic patients and may also reduce toxin production more effectively due to inhibition of bacterial protein synthesis.
In a multicenter study conducted in India (2017), patients treated with both antitoxin and erythromycin within 48 hours had a significantly lower complication rate compared to those treated later or with antibiotics alone.
During a diphtheria outbreak in Indonesia (2017–2018), over 950 cases were reported. A retrospective analysis revealed that patients who received both early antitoxin and antibiotics had a mortality rate below 5%, whereas those who received delayed or no antitoxin had mortality rates exceeding 20%. This demonstrated the synergistic role of prompt, combined therapy and the life-saving impact of early intervention.
Macrolide resistance has been rarely documented but warrants surveillance, especially during outbreaks. In cases of systemic infection or extensive local disease, dual therapy with antitoxin and antibiotics is standard practice.
Supportive Care
Supportive care addresses complications from local and systemic toxin effects. It is especially critical in resource-limited settings, where diphtheria can lead to high mortality.
Airway Management
Severe cases with respiratory distress due to pseudomembrane formation may require:
- Endotracheal intubation
- Emergency tracheostomy
These interventions are life-saving when upper airway obstruction occurs. Continuous monitoring of respiratory status is essential, especially in pediatric patients, who are more susceptible to rapid decompensation.
Cardiac and Neurological Monitoring
The diphtheria toxin may cause myocarditis in 10–25% of cases, with onset usually in the second week of illness. Cardiac monitoring and serial ECGs help detect arrhythmias or conduction blocks early.
Neurological complications, such as cranial nerve palsies or peripheral neuropathy, may require prolonged rehabilitation. Full neurological recovery may take weeks to months.
Nutritional and Fluid Support
Patients with pharyngeal diphtheria often struggle with swallowing (dysphagia), requiring:
- IV fluids or enteral feeding
- Soft or liquid diets
- Monitoring for aspiration risk
Hospitalization is required in nearly all symptomatic cases, with the average length of stay ranging from 7 to 14 days, depending on severity.
Prevention and Vaccination
Preventing diphtheria primarily relies on vaccination and maintaining high immunization coverage within populations. Understanding the vaccine type, the recommended immunization schedule, and herd immunity principles is critical to controlling the disease.
Diphtheria Vaccine
The diphtheria vaccine is a toxoid vaccine, meaning it contains an inactivated form of the diphtheria toxin. This toxoid stimulates the immune system to produce neutralizing antibodies, providing protection against the harmful effects of the toxin, though not necessarily against colonization or asymptomatic carriage.
It is typically administered in combination with vaccines for tetanus and pertussis:
- DTaP (diphtheria, tetanus, acellular pertussis) for children under 7
- Tdap (tetanus, diphtheria, acellular pertussis) as a booster for older children, adolescents, and adults
- DT or Td in cases where pertussis coverage is not included
The vaccine has significantly reduced the global burden of diphtheria. According to WHO, diphtheria incidence decreased by over 90% globally between 1980 and 2019 due to widespread immunization.
Immunity declines over time, especially in adults, necessitating booster doses every 10 years. Studies indicate that approximately 60–70% of adults over age 40 in some countries have sub-protective antibody levels, underlining the importance of adult boosters.
Common adverse effects include low-grade fever, local pain, and swelling at the injection site. Severe reactions, such as anaphylaxis, are extremely rare — estimated at less than 1 per million doses.
Immunization Schedule
The typical immunization schedule includes a primary series of 3 to 5 doses starting at 2 months of age. For example:
| Age | Dose |
|---|---|
| 2 months | 1st dose DTaP |
| 4 months | 2nd dose DTaP |
| 6 months | 3rd dose DTaP |
| 15–18 months | 4th dose DTaP |
| 4–6 years | 5th dose DTaP |
| 11–12 years | Tdap booster |
| Every 10 years | Td booster |
Adults should receive a Td or Tdap booster every 10 years or after potential exposure. Catch-up schedules are available for unvaccinated or incompletely vaccinated individuals, with prioritization during outbreaks or in refugee populations.
In maternal health, a Tdap booster during the third trimester of pregnancy is recommended to provide passive immunity to newborns, who are most at risk.
Herd Immunity
Herd immunity for diphtheria is achieved when a sufficiently large portion of the population is immunized, thereby reducing transmission and indirectly protecting unvaccinated or immunocompromised individuals.
- Coverage rates above 85–90% are required to maintain herd immunity.
- In countries with lower coverage, outbreaks can occur, especially in crowded or displaced communities.
A study in Ukraine (2010–2018) linked declining DTP3 coverage (dropping below 70%) to a resurgence of diphtheria cases in certain oblasts. Similarly, the 2017–2019 outbreak in Venezuela, which reported over 2,700 confirmed cases and more than 280 deaths, was associated with declining vaccine access and coverage due to political and economic instability.
In 2017, a major outbreak occurred among Rohingya refugees in Cox’s Bazar, Bangladesh. Over 8,500 suspected cases were reported, with hundreds of hospitalizations and more than 40 deaths. Investigations revealed that fewer than 50% of the children had received basic immunizations prior to displacement.
A mass immunization campaign using pentavalent (DTP-HepB-Hib) and Td vaccines was launched in coordination with WHO, UNICEF, and GAVI. Follow-up data showed that case incidence dropped significantly within three months of the campaign’s initiation, demonstrating the effectiveness of targeted vaccine interventions even in emergency settings.
Despite global progress, gaps in immunization remain:
- According to WHO/UNICEF estimates, in 2022, more than 14 million children worldwide missed out on basic DTP3 vaccination.
- Countries with the highest numbers of unvaccinated children include Nigeria, India, Democratic Republic of Congo, and Ethiopia.
Diphtheria in Special Populations
Certain populations experience distinct risks and outcomes from diphtheria. Factors such as immune system development, comorbidities, and access to care influence disease progression and response to treatment.
Children and Infants
Young children, particularly those under five years old, are at the highest risk of severe outcomes from diphtheria. The relative immaturity of their immune systems limits their ability to neutralize the diphtheria toxin efficiently. Furthermore, airway anatomy in infants makes them more susceptible to life-threatening respiratory obstruction from pseudomembrane formation.
- Infants under 12 months are especially vulnerable due to incomplete vaccination. Protection during early infancy relies on transplacental maternal antibodies, which wane within the first few months of life.
- According to the World Health Organization (2022), children under 5 accounted for nearly 50% of diphtheria deaths globally in low- and middle-income countries.
Clinical features in children may include:
- High-grade fever
- Cervical lymphadenopathy and “bull neck”
- Rapid progression to respiratory distress
- Neurological complications such as palatal paralysis
Management in pediatric cases requires:
- Urgent antitoxin administration (often at higher doses per kilogram than adults)
- Careful airway monitoring
- Nutritional support in cases with dysphagia
WHO guidelines recommend starting the DTaP series at 6 weeks of age in endemic or high-risk areas, with catch-up vaccination programs targeting children up to 7 years old.
Immunocompromised Individuals
Individuals with impaired immune function are at increased risk for severe, prolonged diphtheria infections. The body’s reduced ability to mount a humoral (antibody-mediated) response compromises the neutralization of the diphtheria toxin.
This population includes:
- HIV/AIDS patients
- Organ transplant recipients
- Cancer patients undergoing chemotherapy
- Individuals on long-term corticosteroids or immunosuppressive therapies
A study on diphtheria cases in sub-Saharan Africa (2010–2018) revealed that HIV-positive individuals were 2.4 times more likely to develop myocarditis and neurologic complications than immunocompetent patients.