Diphtheria

Etiology

Corynebacterium diphtheriae organisms are non–spore-forming, gram-positive bacilli that lack motility and a capsule. Microscopically, the organism characteristically appears in palisade formations or angular arrangements resembling V- or L-shapes.[2] Respiratory tract diphtheria is most commonly associated with toxigenic strains of C diphtheriae. The 4 recognized biotypes are gravis, intermedius, mitis, and belfanti, all of which have been implicated in both endemic disease and outbreak settings.[2]

Other Corynebacterium spp may also produce diphtheria-like illness. Corynebacterium ulcerans is primarily associated with cutaneous disease but has occasionally been reported as a cause of respiratory tract diphtheria. In some cases, infection can progress to severe toxin-mediated illness requiring prompt treatment with diphtheria antitoxin and appropriate antimicrobial therapy, including macrolides. Unlike C diphtheriae, C ulcerans is considered a zoonotic pathogen, and evidence supporting sustained person-to-person transmission remains limited.[3][CDC. Toxigenic Corynebacterium ulcerans in Humans and Household Pets]

Epidemiology

Transmission and Reservoir

Corynebacterium diphtheriae organisms spread primarily through respiratory secretions from infected individuals or asymptomatic carriers.[1] Transmission occurs mainly via respiratory droplets, while direct contact with cutaneous lesions may also contribute. Humans are the primary reservoir, with colonization occurring predominantly in the upper respiratory tract. No clear racial or sex predilection has been consistently demonstrated. Disease outcomes are influenced primarily by immunization status, access to antitoxin, early diagnosis, and supportive care. Diphtheria occurs year-round but is more common during colder months in temperate climates.[4]

Global Burden of Disease

Before widespread vaccination, diphtheria was a major cause of childhood morbidity and mortality worldwide. Routine immunization with diphtheria toxoid led to a marked decline in incidence and transformed the disease into a rare infection in many resource-rich countries.[5] Despite these advances, diphtheria remains endemic in parts of Africa, Asia, the Middle East, and Latin America, particularly in regions with low vaccine coverage, limited healthcare access, humanitarian crises, or population displacement. Recent outbreaks in Europe, Africa, and Latin America highlight the continued risk of reemergence when herd immunity declines.[6][7]

Historically, diphtheria primarily affected children younger than 12 years. Following widespread childhood vaccination, disease epidemiology shifted toward adolescents and adults, particularly individuals with incomplete immunization or waning immunity. Adults older than 40 years now account for an increasing proportion of cases in many settings.[8]

Risk factors for infection include:

• Lack of vaccination or incomplete immunization
• Failure to receive booster doses
• Waning antitoxin immunity
• Residence in endemic areas
• International travel to regions with active transmission
• Crowded living conditions, homelessness, and refugee settings
• Exposure to infected individuals or asymptomatic carriers
• Limited healthcare access and disrupted public health infrastructure [4][9]

Pathophysiology

The clinical manifestations of diphtheria result from both localized infection and the effects of diphtheria exotoxin. Diphtheria typically involves the respiratory tract mucosa or skin, producing local inflammation and tissue injury, while systemic complications arise from hematogenous dissemination of the toxin.[4] Virulence depends primarily on the production of diphtheria toxin by toxigenic strains of Corynebacterium diphtheriae. Toxin synthesis occurs only when the organism is infected by a lysogenic bacteriophage carrying the tox gene. Nontoxigenic strains generally cause milder disease and are less likely to produce severe systemic complications.[10]

Diphtheria toxin is composed of subunits A and B. The B subunit mediates attachment to host cells by binding to the heparin-binding epidermal growth factor–like precursor, which serves as the cellular receptor. Following receptor-mediated endocytosis, the toxin enters the cytoplasm, where the A subunit exerts enzymatic activity. The catalytic fragment transfers adenosine diphosphate-ribose from nicotinamide adenine dinucleotide to elongation factor 2, thereby inhibiting protein synthesis and leading to cell death.[2][10]

At the site of infection, the host's inflammatory response, combined with toxin-mediated tissue necrosis, results in the formation of the characteristic gray-white pseudomembrane involving the tonsils, pharynx, or larynx. This membrane consists of necrotic epithelial cells, fibrin, inflammatory cells, and bacterial colonies and may contribute to airway obstruction in severe cases.[7] Local tissue injury facilitates lymphatic and vascular spread of the toxin to distant organs. The myocardium and peripheral nervous system are particularly susceptible to toxin-mediated damage, leading to complications such as myocarditis, conduction abnormalities, cranial neuropathies, and peripheral neuropathy. Renal injury and other systemic manifestations may also occur in severe disease. The extent of toxin production and host immunity largely determines disease severity and clinical outcome.[2][10]

History and Physical

History

Infection caused by Corynebacterium diphtheriae most commonly presents as respiratory or cutaneous diphtheria. Although disease is frequently localized, toxin-mediated systemic complications may involve the cardiovascular, neurologic, and renal systems, resulting in myocarditis, neuropathies, and kidney injury. The incubation period is generally 2 to 5 days, with a range of 1 to 10 days. Clinicians should obtain travel history to endemic regions and vaccination status, particularly in areas where diphtheria is uncommon.

Respiratory diphtheria classically presents with the formation of a thick, gray, adherent pseudomembrane involving the tonsils, pharynx, or larynx. Early findings often include mild pharyngeal erythema that progresses to membrane formation. The pseudomembrane consists of fibrin, necrotic epithelial cells, inflammatory cells, erythrocytes, leukocytes, and bacterial debris. Removal of the membrane frequently causes bleeding because of its firm attachment to the underlying tissue.[11] Common symptoms include low-grade fever, sore throat, malaise, cervical lymphadenopathy, and headache.[4]

Marked cervical lymphadenopathy and soft-tissue edema may produce the characteristic bull-neck appearance. Airway obstruction due to extensive pseudomembrane formation is a major cause of mortality. Cutaneous diphtheria typically appears as chronic, nonhealing ulcerative lesions covered by a gray membrane. These lesions usually remain localized without deep tissue invasion and often develop in areas of prior skin injury, trauma, or underlying dermatologic disease.[12]

Physical Examination

Patients typically exhibit a low-grade fever but appear toxic, often accompanied by a swollen neck. General symptoms include fever, tachycardia, halitosis, and anxiety. A thick, gray, leathery membrane covers the tonsils, oropharynx, soft palate, nasopharynx, and uvula (see Image. Diphtheria in the Oral Cavity). Scraping the pseudomembrane causes bleeding of the underlying mucosa. A patient may hold the head extended due to a bull neck. Dysphonia may occur occasionally. Respiratory distress manifests as stridor, wheeze, cyanosis, and retractions.[9] Cardiac involvement usually occurs 1 to 2 weeks into the illness, following improvement in the pharyngeal phase.[13] Cardiac involvement may manifest as follows:

• Myocarditis can present acutely with congestive heart failure and circulatory collapse. Patients can have more subtle features, such as progressive dyspnea, cardiac chamber dilatation, diminished heart sounds, and weakness.[14]
• Electrocardiographic changes may include ST segment and T wave changes, atrioventricular blocks, and various dysrhythmias.
• Endocarditis may occur, particularly in the presence of an artificial valve.[15] 

Neurological involvement depends on the extent of the pharyngeal infection. Deficits include the following:

• Cranial nerve deficits
• Stocking and glove peripheral sensory neuropathy
• Peripheral neuritis [16]

Evaluation

Diphtheria is primarily a clinical diagnosis supported by microbiologic confirmation. Suspected cases require immediate isolation, notification of public health authorities, and prompt treatment; therapy should not be delayed while awaiting confirmation.[CDC. Guidance for Diphtheria]

Microbiologic Evaluation

When diphtheria is suspected, culture of the site of infection, such as the throat, nasopharynx, pseudomembrane, or skin wound, should be performed. Specimens should be collected before antibiotics are started, when feasible. Clinicians should notify the laboratory when diphtheria is suspected so appropriate selective or enrichment media can be used.  

Colonies of gram-positive bacilli isolated on culture can then be further identified by additional tests, including biochemical assays, matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry, or polymerase chain reaction (PCR).[17]. Culture may be performed on media such as Löffler medium, cystine-tellurite blood agar, Tinsdale medium, or tellurite-containing agar, which support the isolation of Corynebacterium diphtheriae.[CDC. Laboratory Testing for Diphtheria]

Toxigenicity testing: If C diphtheriae is isolated, further testing is required to determine whether the strain is toxigenic. Testing usually involves detection of the diphtheria toxin gene by polymerase chain reaction and confirmation of actual toxin production, most commonly by the Elek immunodiffusion test or another validated toxin-production assay. Identification of C diphtheriae alone, or detection of the tox gene alone, is insufficient to confirm toxigenic diphtheria because some strains carry the gene but do not produce toxin. Testing is typically coordinated through local or state public health laboratories, with CDC support in the US [CDC. Clinical Guidance for Diphtheria].

Additional Evaluation for Complications

• Complete blood count:
• May show leukocytosis
• Nonspecific finding
• Cardiac evaluation (if myocarditis suspected):
• Electrocardiography
• Troponin levels
• Echocardiography for heart failure, conduction abnormalities, or hemodynamic instability
• Imaging (when clinically indicated):
• Chest radiography for pneumonia or aspiration
• Neck imaging for airway compromise

Serology

• Diphtheria antitoxin serology may assess immune status
• Not recommended for the diagnosis of acute infection

Treatment / Management

The primary treatment approaches for diphtheria involve prompt administration of diphtheria antitoxin and antibiotics. Clinicians should also perform a thorough assessment for potential respiratory and cardiovascular instability. In suspected cases of diphtheria, antitoxin should be administered urgently based on clinical judgment without waiting for laboratory confirmation. Suspected cases must be isolated, and stringent droplet precautions should be implemented. Additionally, clinicians should evaluate the patient for signs of respiratory distress, and airway protection is imperative when indicated. Early management also involves continuous cardiac monitoring to address potential cardiovascular complications.

Diphtheria Antitoxin 

Diphtheria antitoxin, derived from horse antiserum, is crucial for treatment.[18] The antitoxin neutralizes unbound diphtheria toxin circulating in the blood. However, the antitoxin becomes ineffective once the toxin has bound to the cell membrane. The antitoxin dose is tailored to the patient's clinical state and the severity of the condition, and it can be administered intramuscularly or intravenously. Before antitoxin administration, the patient should undergo hypersensitivity testing, and emergency medications for anaphylaxis must be readily available at the bedside.[4](A1)

Antibiotic Treatment

The antibiotics of choice for treating diphtheria are erythromycin or penicillin G.[19] Erythromycin is prescribed at a dose of 500 mg 4 times daily for 2 weeks. Penicillin G is administered intramuscularly at a dose of 300,000 units every 12 hours for patients weighing 10 kg or less and 600,000 units every 12 hours for those weighing more than 10 kg. Once the patient is able to take oral medication, oral penicillin V can be initiated at 250 mg 4 times daily for 2 weeks. Early initiation of antibiotics is crucial to promptly eliminate the organism, limit toxin release, expedite patient recovery, and prevent the infection from spreading to close contacts. In cases of antibiotic resistance, linezolid or vancomycin may be considered.(A1)

Close contacts, including household members and individuals in direct contact with the infected patient, should receive postexposure prophylaxis. Healthcare professionals exposed to a patient's respiratory secretions should also receive postexposure prophylaxis. Postexposure prophylaxis involves a single dose of penicillin G administered as follows:

• 600,000 units intramuscularly for individuals younger than 6 years
• 1.2 million units intramuscularly for individuals aged 6 years and older [20]
(B3)

Alternatively, oral erythromycin can be given at a dose of 500 mg 4 times daily for 7 to 10 days. Timely, comprehensive antibiotic treatment is essential for treating infected individuals, preventing potential outbreaks, and minimizing the risk of complications within the broader community.

Differential Diagnosis

Distinguishing diphtheria from other upper respiratory tract infections with similar presentations is crucial. Relevant differential diagnoses to consider during the diagnostic process include the following:

• Epiglottitis: Characterized by acute inflammation of the epiglottis and surrounding structures.[21][22]
• Retropharyngeal abscess: Manifests with high-grade fever and requires urgent drainage.[23]
• Angioedema: Presents as generalized swelling involving the lower dermis and subcutaneous or submucosal tissues.[24]
• Infectious mononucleosis: Features include fatigue, malaise, sore throat, fever, nausea, anorexia, and cough. The classic presentation in children includes fever, pharyngitis, and lymphadenopathy.[25][26]
• Pharyngitis: Exhibits sudden onset of sore throat, odynophagia, fever, and cough.[27]
• Oral candidiasis: The grayish pseudomembrane in diphtheria must be differentiated from the whitish appearance of oral candidiasis.[28][29]
• Vincent angina: Involves infection of the gums, presenting with painful, bleeding gums and ulcerative gingiva necrosis.

Prognosis

Although overall mortality has declined substantially since vaccine introduction, diphtheria remains associated with significant morbidity and mortality when diagnosis or treatment is delayed. Reported case-fatality rates are approximately 5% to 10%, although mortality may exceed 20% among children younger than 5 years and adults older than 40 years.[20][30][31] Most deaths result from airway obstruction caused by pseudomembrane formation or toxin-mediated complications, particularly myocarditis. Invasive disease with bacteremia carries substantially higher mortality rates.[31][32]

Complications

The primary complications of diphtheria often involve myocarditis and neuritis.[30][31] Fatality occurs in 5% to 10% of cases. Another critical complication is pseudomembrane formation in the upper respiratory tract, which can cause respiratory obstruction and necessitate urgent mechanical ventilation and intubation.[32]

Cardiac Complications

Diphtheria can manifest with myocarditis, characterized by cardiac arrhythmias that may present as first-, second-, or third-degree heart block and often lead to circulatory collapse.[33] Electrocardiogram  changes in affected patients include a prolonged PR interval, ST segment and T wave changes.[13][34]

Neurologic Complications

Neurological complications in diphtheria include nerve weakness or paralysis, particularly involving the cranial nerves and peripheral nerves, leading to extremity muscle weakness. Pharyngeal muscle and soft palate involvement can result in regurgitation of foods and fluids through the nose. Although uncommon, encephalitis stemming from diphtheria complications can manifest in children.[35]