Diphtheria

Etiology

C diphtheriae is a non–spore-forming gram-positive bacillus characterized by its nonmotile, nonencapsulated nature. Its distinctive club-shaped appearance forms palisades or V- or L-shaped arrangements. Besides C diphtheria, Corynebacterium ulcerans can induce cutaneous diphtheria and, rarely, contribute to respiratory diphtheria cases.[4] 

The pathogenic impact of exotoxins extends to both localized and systemic manifestations of the disease. Viral bacteriophages carry the genetic code for exotoxins, facilitating their transmission among bacteria. Three distinct strains of C diphtheriae—gravis, intermedius, and mitis—have been isolated, and all 3 are capable of toxin production.[5]

The pathogenesis of diphtheria involves various etiological factors, including:

• Incomplete or absent immunization [6]
• Waning immunity over time, rendering older individuals without booster vaccination more susceptible to infection
• Low herd immunity
• Travel to endemic areas
• Travel to regions experiencing current epidemics
• Immunocompromised states
• Low socioeconomic status
• Large-scale population movements
• Overcrowded conditions, such as military barracks, jails, and homeless shelters
• Domestic animals [7]

Epidemiology

Since the implementation of the vaccine, the incidence of the disease has witnessed a rapid decline. Before 1920, the US reported approximately 200,000 annually.[8] However, this number has drastically decreased following the introduction of widespread immunization programs, with only around 1000 cases reported annually. Most cases are observed in individuals with low socioeconomic status, living in overcrowded conditions, lacking immunizations, with a travel history from endemic regions, and having comorbid conditions. These numbers remain higher in certain global regions, particularly Southeast Asia and Africa. Regarding mortality in the US, the figures have decreased from 100 to 200 cases to 0.001 per 100,000 population since the advent of vaccinations.

Reports from the World Health Organization (WHO) suggest that diphtheria epidemics continue to pose a health risk in developing countries. India has experienced a higher incidence of diphtheria, primarily attributed to challenges in implementing widespread vaccination efforts.[9] A significant proportion of the global burden of diphtheria is concentrated in India.[9][10] 

Diphtheria does not exhibit any racial or sexual preference. While diphtheria is commonly recognized as a childhood disease, predominantly affecting those below 12 years, individuals around the age of 40 and those with comorbid conditions are also susceptible to infection. As immunity against the bacteria naturally wanes, the risk of infection rises for individuals not currently receiving immunizations and booster doses.[11]

Pathophysiology

Humans are the primary reservoir for diphtheria infection; nevertheless, case reports suggest a link between diphtheria and livestock.[12] Infected individuals and asymptomatic carriers can act as a source of C diphtheriae transmission through respiratory droplets, nasal secretions, and, rarely, fomites.

Exotoxin production is the primary mechanism through which the organism manifests its distinctive clinical features. The exotoxin is a singular polypeptide composed of 2 subunits, A and B. The B subunit facilitates the toxin binding to the receptor on the cell membrane, while the A subunit possesses enzymatic properties, cleaving nicotinamide from nicotinamide adenine dinucleotide (NAD). This cleavage inhibits protein synthesis through adenosine diphosphate (ADP)-ribosylation of elongation factor 2 (EF-2). The host's response to the bacteria induces local inflammation in the throat and pharynx, giving rise to a resilient, gray pseudomembrane—an identifiable hallmark of the disease.

Local tissue destruction facilitates the lymphatic and hematologic spread of the toxin to various body systems. This diphtheria toxin may damage distant organs, including the kidneys, myocardium, and the nervous system.[13] Infections resulting from nontoxigenic strains generally exhibit milder severity.

History and Physical

Diphtheria typically initiates with nonspecific flu-like symptoms, including fever, sore throat, and cervical lymphadenopathy. The average incubation period spans 2 to 5 days, ranging from 1 to 10. A travel history from an endemic region with no vaccination records is often indicative. In such instances, healthcare practitioners should be alert to the hallmark features of the disease, notably the presence of a thick, gray, adherent pseudomembrane covering the tonsils and throat. Respiratory tract involvement is common, commencing with mild erythema that later evolves into a merging pseudomembrane.

The pseudomembrane comprises red blood cells (RBCs), white blood cells (WBCs), dead cell debris, and organisms. Attempting to scrape it from the adhering surface often results in bleeding. Typical symptoms and signs of diphtheria encompass low-grade fever, sore throat, malaise, cervical lymphadenopathy, headache, and dysphagia. According to a study by Pancharoen C et al, the most common manifestations of diphtheria included patchy lesions, followed by fever and upper respiratory tract infection.[14] Furthermore, systemic involvement occurs as the toxin leaks into the lymphatic and hematologic system following local tissue destruction.

Cervical adenopathy and swollen mucosa often result in a distinctive "bull neck" appearance in many infected patients.[15] The leading cause of mortality is airway obstruction or suffocation, primarily due to the aspiration of the pseudomembrane.

In cutaneous diphtheria, one can observe ulcerating skin lesions covered by a gray membrane. These lesions do not spread or invade surrounding tissues. The site for these cutaneous lesions typically involves previously injured tissues, often stemming from trauma or preexisting dermatologic lesions.[16][17]

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. The patient may hold their head extended due to the bull neck. Occasionally, there can be dysphonia. Respiratory distress manifests as stridor, wheeze, cyanosis, and retractions.

Cardiac involvement occurs after 1 to 2 weeks of illness after improvement in the pharyngeal phase. Cardiact involvment 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.[18]
• ST-T wave changes, atrioventricular blocks, and various dysrhythmias may be evident.
• Endocarditis, particularly in the presence of an artificial valve.[19] 

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[20]

Evaluation

Diagnosing diphtheria involves a combination of clinical evaluation, laboratory tests, and sometimes imaging studies. An overview of the various tests used to evaluate diphtheria are as follows:

Clinical Evaluation

• Throat culture: A swab is taken from the pseudomembrane or any visible lesions for culture to identify C diphtheriae. The throat swab is cultured on specific media to isolate the bacteria. Commonly used media include Löeffler or Tindale medium, telluride plates, and blood agar. The particular characteristics of these mediums indicate the presence of the organism:
  • Tindale medium: C diphtheriae forms a distinctive black colony with halos
  • Löffler medium: Metachromatic granules are observed in the presence of C diphtheriae.
  • Telluride plate: the typical gray-black color of tellurium is indicative of the organism's presence
• Gram stain: Identifying Gram-positive bacilli with characteristic club-shaped appearance can support the diagnosis. Although Gram staining does not confirm the diagnosis, the initial test is performed in suspected cases. The smear is also stained with methylene blue, which reveals the typical metachromatic granules.
• Patient history and physical examination: Travel history, immunization status, and clinical symptoms such as sore throat, fever, and pseudomembrane formation are considered in the diagnosis.

Laboratory Tests

• Toxin detection: Toxin production by the bacteria can be confirmed through laboratory tests, such as the Elek test, polymerase chain reaction (PCR) testing, and enzyme immunoassay (EIA) test.[21]
• Serology: Blood tests can measure antibody levels against diphtheria toxin, providing information about the patient's immune response.

Imaging Studies

• Chest x-ray: If respiratory symptoms or concerns about complications like pneumonia are present, a chest x-ray may be performed to assess lung involvement. This imaging study may reveal swelling of the soft tissue structure in and around the pharynx, epiglottis, and chest. 
• Echocardiogram: In cases of suspected cardiac involvement, an echocardiogram can help assess the function and structure of the heart and possibly reveal valvular vegetation, although this is a rare phenomenon.[22]

Other Laboratory Studies

• CBC: An elevated WBC may indicate an inflammatory response. 
• Troponin level: This study may be beneficial to assess the extent of the myocardial injury.[23]

Treatment / Management

The primary treatment approaches for diphtheria involve promptly administering antitoxins and antibiotics. Additionally, the patient should undergo a thorough assessment for potential respiratory and cardiovascular instabilities. 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. Furthermore, the patient should be evaluated for signs of respiratory distress, and ensuring an airway is imperative. Early management also involves continuous cardiac monitoring to address any potential cardiovascular complications.

Diphtheria Antitoxin 

Diphtheria antitoxin (DAT), derived from horse antiserum, is crucial in treatment.[24] Antitoxin functions by neutralizing unbound diphtheria toxin circulating in the blood. The antitoxin becomes ineffective once the toxin has bound to the cell membrane. The dosage of antitoxin 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 anaphylaxis medication must be readily available at the bedside.(B3)

Antibiotic Treatment

The antibiotics of choice for treating diphtheria are erythromycin or penicillin G.[25] Erythromycin is prescribed at a dose of 500 mg 4 times a day for a 2-week duration. Penicillin G is administered intramuscularly, with a dosage 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 can take oral medication, oral penicillin V can be initiated at a dose of 250 mg 4 times daily for 2 weeks. Early initiation of antibiotics is crucial to eliminate the organism promptly, limiting toxin release, expediting patient recovery, and preventing infection spread 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 contact prophylaxis. Medical staff exposed to a patient's respiratory secretions should also undergo prophylaxis. Contact prophylaxis involves a single dose of penicillin G administered as follows:[26](B3)

• 600,000 units intramuscularly for individuals younger than 6 years
• 1.2 million units intramuscularly for individuals 6 or older

Alternatively, oral erythromycin can be given at a dose of 500 mg 4 times a day for 7 to 10 days. Ensuring timely and comprehensive antibiotic treatment is essential for the individual patient, preventing potential outbreaks and minimizing the risk of complications in the broader community.

Differential Diagnosis

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

• Epiglottitis: Characterized by acute inflammation of the epiglottis and surrounding structures.[27][28]

• Retropharyngeal abscess: Manifests with high-grade fever and requires urgent drainage.[29]

• Angioedema: Presents as generalized swelling involving the lower dermis and subcutaneous/submucosal tissues.[30]

• Infectious mononucleosis: Features fatigue, malaise, sore throat, fever, nausea, anorexia, and cough. The classic presentation in children includes fever, pharyngitis, and lymphadenopathy.[31][32]

• Pharyngitis: Exhibits sudden onset of sore throat, odynophagia, fever, and cough.[33]

• Oral candidiasis: The grayish pseudomembrane in diphtheria must be differentiated from the whitish appearance of oral candidiasis.[34][35]

• Vincent angina: Involves infection of the gums, presenting with painful, bleeding gums and ulcerative gingiva necrosis.

Prognosis

The prognosis of diphtheria is influenced by several factors:

• High mortality rates are observed in individuals younger than 5 and those older than 40.

• Cases with an onset duration exceeding 4 days are associated with elevated mortality.

• Cardiovascular involvement, particularly atrioventricular and left bundle-branch blocks, is associated with a poor prognosis.

• Systemic involvement is a significant predictor of high mortality rates.[36]

Complications

The primary complications of diphtheria often involve myocarditis and neuritis.[37][38] Fatality occurs in 5% to 10% of cases. Another critical complication arises from pseudomembrane formation in the upper respiratory tract, potentially causing respiratory obstruction, necessitating urgent mechanical ventilation and intubation.[39]

Cardiac Complications

Diphtheria can manifest with myocarditis characterized by cardiac arrhythmias, present as first, second, or third-degree heart block, often leading to circulatory collapse.[23] Electrocardiogram (ECG) changes in affected patients include a prolonged P-R interval and ST and T wave changes.

Neurologic Complications

Neurological complications in diphtheria include nerve weakness or paralysis, particularly involving the cranial nerves and affecting the nerves in the extremities, leading to muscle weakness in the extremities. The involvement of the pharyngeal muscles and the soft palate can result in regurgitating foods and fluids through the nose. While uncommon, encephalitis stemming from diphtheria complications can manifest in children.[40]