How to Cite This Chapter: Attalla M, Szymczak A. Diphtheria. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. https://empendium.com/mcmtextbook/chapter/B31.II.3.67. Accessed May 30, 2024.
Last Updated: November 17, 2021
Last Reviewed: November 17, 2021
Chapter Information

Definition, Etiology, PathogenesisTop

Diphtheria is a rare (<5 cases per year in Canada) acute bacterial infection caused by Corynebacterium diphtheriae that usually affects the upper respiratory tract or skin. In some cases it may lead to cardiac, central nervous system (CNS), or renal complications.

1. Etiologic agent: C diphtheriae, a gram-positive, nonencapsulated, aerobic bacillus that does not form spores.

2. Pathogenesis: The bacteria multiply at the port of entry and produce an exotoxin, which causes localized lesions in the respiratory epithelium, leading to the development of pseudomembranes, and spreads to organs distant from the site of infection via blood and the lymphatic system. The toxin inhibits protein synthesis, resulting in cell death. Nontoxigenic C diphtheriae strains cause invasive disease.

3. Reservoir and transmission: Humans are the only reservoir for C diphtheriae, including those with active infection, convalescents, and carriers. Infection is usually transmitted by respiratory droplets or less frequently by direct contact with respiratory secretions or discharge from ulcerations.

4. Incubation and contagious period: The incubation period is on average 2 to 4 days (1-10 days). The patient is contagious in the last 2 days of the incubation period, during the entire symptomatic period, and for 4 days following the resolution of diphtheria—in those receiving treatment. In those untreated, diphtheria infection can last up to 2 to 3 weeks, rarely 6 weeks. In patients with cutaneous diphtheria, the contagious period is considerably longer due to discharge from ulcers.

Clinical FeaturesTop

In vaccinated persons diphtheria has a milder course and the risk for organ damage is low. Characteristic features of diphtheria include grayish-brown pseudomembranes firmly adherent to the respiratory mucosa, which bleed on attempts of removal (eg, with a tongue depressor).

General manifestations: Symptoms usually begin as sore throat, general malaise, cervical lymphadenopathy, and low-grade fever.

Respiratory Diphtheria

Respiratory diphtheria usually begins 2 to 5 days after infection by the toxin-producing strains of C diphtheriae. The pharynx is involved in two-thirds of cases. Involvement of the larynx, nasal passage, and tracheobronchial tree is less common.

Pharyngeal Diphtheria

The most frequent symptoms of pharyngeal diphtheria are mild erythema (which can be associated with white spots and gray exudates), halitosis, sore throat, dysphagia, excessive salivation, and painful local lymphadenopathy.

In severe cases, massive soft tissue edema can develop in the tonsils, uvula, cervical lymph nodes, submandibular soft tissue, and anterior neck (frequently described as “bull’s neck”), and cause stridor. In patients who develop airway obstruction, additional respiratory muscles can become involved and cyanosis can develop. Urgent airway stabilization should be established in these cases.

A pseudomembrane can develop after 2 to 3 days and cover the tonsils, posterior pharyngeal wall, and soft palate. When this occurs, there is a high risk of aspirating the fragments, which can be fatal. The pseudomembrane is initially white and then turns grayish-brown. Once this develops, there is an increased risk for systemic toxicity.

Nasal Diphtheria

Nasal diphtheria manifests with serosanguineous, purulent, or sanguinopurulent nasal discharge and localized pseudomembranes forming mainly on the nasal septum. Other systemic manifestations are rare.

Laryngeal and Tracheal Diphtheria

Laryngeal infection usually spreads from pharyngeal diphtheria, but it can occur in isolation. Pseudomembranes and mucosal edema lead to airway obstruction. Symptoms include hoarseness, aphonia, inspiratory wheeze, a loud barking cough, and dyspnea.

Cardiac Complications

Myocarditis (clinically apparent in 10%-25% of patients), arrhythmia, conduction disturbances, and acute heart failure. These usually develop after 1 to 2 weeks of the onset of symptoms of diphtheria and manifest as ST-segment changes, QTc prolongation, or first-degree heart block, which can be detected in two-thirds of cases. The risk of developing cardiac complications is proportional to the severity of illness and its onset usually occurs 7 to 10 days after respiratory symptoms improve. Severe myocarditis is a significant cause of mortality in diphtheria. The occurrence of cardiomyopathy is more likely in patients who develop severe pseudomembrane. Nontoxigenic C diphtheriae can cause endocarditis or mycotic aneurysms.

CNS Complications

Neurologic toxicity can occur in 5% of patients with mild disease and in 75% of patients with severe disease. Paralysis of the soft palate and posterior pharyngeal wall is followed by cranial neuropathies. Peripheral neuropathies can occur weeks to months later and can include paralysis of respiratory muscles, sensory neuropathy, and the stock-and-glove pattern.

Neurologic manifestations (particularly bulbar palsy) frequently appear as early as in the first days of diphtheria. Peripheral sensory and motor neuropathy develops in weeks 3 to 6 of the disease. The symptoms usually resolve slowly over a number of weeks without permanent sequelae. The severity of membrane formation correlates with the onset of symptoms and delay in administration of antitoxin.

Renal Involvement

Tubular necrosis can develop in patients with severe systemic diphtheria.

Cutaneous Diphtheria

Cutaneous diphtheria can develop in toxic and nontoxic forms of C diphtheriae. Generalized symptoms are rarely associated with cutaneous diphtheria. However, skin ulcers can be a reservoir for spreading diphtheria to susceptible hosts, particularly in regions with low vaccine uptake. Cutaneous diphtheria is characterized by nonhealing shallow ulcers with a gray membrane or filled with necrotic debris. Pre-existing dermatoses can become colonized with diphtheria, and cutaneous diphtheria can present in such pre-existing skin lesions and is often preceded by trauma. Risk factors for developing cutaneous diphtheria include low socioeconomic status and poor access to health care.

Other Organ Involvement

Other mucous membranes including conjunctiva, vagina, and rectum may be involved. Osteomyelitis and septic arthritis can also develop.

Invasive Disease

Invasive disease develops rarely and is most often found in alcohol or illicit IV drug users. It may manifest as endocarditis, osteomyelitis, septic arthritis, and mycotic aneurysm.


Diagnostic Tests

1. Identification of the etiologic agent:

1) Direct smear from the pseudomembranes, which may provide presumptive diagnosis.

2) Cultures: Cultures are grown using the Loeffler medium or tellurite agar (specimens: nasopharyngeal swab, pseudomembrane fragments, deep swabs from ulcerations in patients with cutaneous diphtheria). Inform a microbiology laboratory about the suspected diphtheria case to obtain appropriate mediums.

3) Toxin detection: Testing for toxin production is required to differentiate toxigenic from nontoxigenic strains of C diphtheriae. A polymerase chain reaction (PCR) test can be used to detect the toxin gene, but this does not indicate whether toxin is being produced and therefore should be confirmed by culture.

2. Other tests:

1) Examination of cerebrospinal fluid in patients with neurologic abnormalities (increased protein concentrations with a normal cell count).

2) Cardiac troponin measurement.

3) Electrocardiography (ECG): ST-segment elevation, atrioventricular block of various degree, right bundle branch block, atrioventricular dissociation, and ventricular arrhythmias.

Diagnostic Criteria

In patients with typical respiratory tract involvement, presumptive diagnosis is based on clinical features. The diagnosis should be confirmed by microbiologic studies from respiratory secretions or cutaneous lesions. Other laboratory studies are usually nonspecific and may demonstrate an elevated white blood cell count and proteinuria.

Differential Diagnosis

Infectious mononucleosis, acute pharyngitis, tonsillitis, peritonsillar abscess, retropharyngeal abscess, acute epiglottitis due to Haemophilus influenzae infection, oral candidiasis, esophageal candidiasis, foreign body in the respiratory tract.


Patients with suspected diphtheria should be urgently admitted to a high acuity unit allowing prolonged monitoring of respiratory and cardiac function. Treatment options include antibiotic therapy and antitoxin for severe cases. Airway management is important for preventing the risk of airway obstruction. Serial ECGs and measurement of cardiac enzymes should be done to monitor for cardiac complications. Neurologic status should also be carefully monitored.

Treatment of Diphtheria

1. Equine diphtheria antitoxin: Diphtheria antitoxin should be administered as soon as possible and should not be delayed to await the results of microbiologic studies. The dose depends on the severity of illness and should be administered IV over 60 minutes.

1) Pharyngeal or laryngeal diphtheria: 20,000 to 40,000 units IV.

2) Nasopharyngeal diphtheria: 40,000 to 60,000 units IV.

3) Severe infection or delayed treatment (initiated after >3 days from onset): 80,000 to 120,000 units IV.

There is a 10% risk of hypersensitivity reaction and serum sickness. Epinephrine should be readily available in case anaphylaxis develops.

2. Antibiotic therapy: Antibiotic therapy kills the microorganism, thus preventing further formation of toxin, slowing the spread of local infection, and reducing transmission. Use penicillin G procaine (INN procaine benzylpenicillin) 12,500 to 25,000 IU/kg bid (maximum, 1.2 million IU/d) IM or erythromycin 10 to 12.5 mg/kg qid IV or orally for 14 days. Alternatively, you may use rifampin (INN rifampicin) or clindamycin. In patients with invasive disease, use IV penicillin or ampicillin in combination with an aminoglycoside for 4 to 6 weeks. Vancomycin or linezolid can be used as alternative antibiotic agents if there is antibiotic resistance. Repeat cultures should be obtained 2 weeks after completion of therapy.

3. Vaccination against diphtheria: Diphtheria vaccine is administered after completion of treatment (the disease does not protect from reoccurrence).

Symptomatic Treatment

Symptomatic treatment depends on the type and complications of diphtheria and may include:

1) Mechanical removal of pseudomembranes causing airway obstruction.

2) Prevention of airway obstruction by early intubation.

3) Cardiac pacing in patients with severe arrhythmia or conduction disturbances.

4) Replacement of the infected valve may be required in patents with endocarditis.

5) Feeding through a nasogastric tube with elevation of the upper part of the body in patients with paralysis of throat muscles.


Airway obstruction, cardiac complications (heart failure, sudden cardiac death, persistent conduction disturbances, valvular damage), bacterial pneumonia, serum sickness as an adverse effect of antitoxin treatment.


Specific Prevention

1. Vaccination: Note that vaccination does not protect from invasive disease.

2. Postexposure prophylaxis in persons with a recent history of contact with a patient with diphtheria:

1) Booster diphtheria vaccination appropriate for the patient’s age if the previous vaccination dose was administered >5 years before exposure.

2) Antimicrobial prophylaxis (after collecting nose and throat swabs for microbiologic studies): Oral erythromycin for 7 to 10 days or a single dose of IM penicillin G (INN benzylpenicillin; 1.2 million IU in patients aged ≥6 years, 600,000 IU in patients <6 years). Microbiologic tests should be repeated 2 weeks after discontinuation of antimicrobial prophylaxis. Do not use diphtheria antitoxin as part of postexposure prophylaxis.

3. Treatment of diphtheria carriers: As in antimicrobial prophylaxis.

Infection Control Precautions

Patient isolation: Patients should be isolated until 2 negative culture results from the respiratory tract are obtained at a 24-hour interval after discontinuation of antimicrobial treatment.

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