Clinical manifestations, diagnosis, and treatment of diphtheria

INTRODUCTION — Diphtheria is an infectious disease caused by the gram-positive bacillus Corynebacterium diphtheriae. Infection may lead to respiratory disease, cutaneous disease, or an asymptomatic carrier state. The word diphtheria comes from the Greek word for leather, which refers to the tough pharyngeal membrane that is the clinical hallmark of infection [1].

The clinical manifestations, diagnosis, and treatment of diphtheria will be reviewed here. The epidemiology, pathophysiology, and prevention of this infection are discussed separately. (See "Epidemiology and pathophysiology of diphtheria" and "Tetanus-diphtheria toxoid vaccination in adults" and "Diphtheria, tetanus, and pertussis immunization in children 7 through 18 years of age" and "Diphtheria, tetanus, and pertussis immunization in children 6 weeks through 6 years of age".)

CLINICAL MANIFESTATIONS — Infection with C. diphtheriae typically presents as respiratory or cutaneous disease. Systemic manifestations involving the heart (myocarditis), nervous system, and kidneys can also occur. Rarely, diphtheria presents as vaginal, conjunctival, or otic infection.

Respiratory diphtheria — Respiratory diphtheria is typically caused by toxin-producing strains of C. diphtheriae; rarely, it is caused by toxigenic strains of other Corynebacterium species (C. ulcerans, C. hemolyticum, or C. pseudotuberculosis) [2]. Symptoms typically begin two to five days after infection. In addition to respiratory symptoms, absorption and dissemination of diphtheria toxin can lead to toxin damage of the heart (myocarditis), nervous system, and kidneys.

The onset of symptoms is typically gradual; the most common presenting symptoms are sore throat, malaise, cervical lymphadenopathy, and low-grade fever. The earliest pharyngeal finding is mild erythema, which can progress to isolated spots of gray and white exudate. In at least one-third of cases, local elaboration of toxin induces the formation of a coalescing pseudomembrane (composed of necrotic fibrin, leukocytes, erythrocytes, epithelial cells, and organisms) (picture 1 and picture 2). This membrane adheres tightly to the underlying tissue and bleeds with scraping.

This membrane can extend to any portion of the respiratory tract from the nasal passages to the tracheobronchial tree. Up to two-thirds of cases are tonsillopharyngeal; involvement of the laryngeal, nasal, and tracheobronchial areas is less common [3]. Systemic toxicity increases as the pseudomembrane spreads from the tonsillopharyngeal area. A form of malignant diphtheria is associated with extensive "membranous pharyngitis" plus massive swelling of the tonsils, uvula, cervical lymph nodes, submandibular region, and anterior neck (the so-called "bull neck" of toxic diphtheria). In such cases, respiratory stridor may ensue, leading to respiratory insufficiency and death. In addition, aspiration of the membrane can lead to suffocation.

In untreated patients, the infectious period begins at symptom onset and lasts for two weeks in the majority of patients; in some cases, it can last as long as six weeks. In patients treated with appropriate antibiotics, the infectious period usually lasts less than four days.

Other respiratory tract symptoms vary with the site of involvement:

●Patients with nasal diphtheria usually experience mild disease and present with a serosanguineous/purulent nasal discharge, which can cause mild irritation of the external nares and upper lip.

●Laryngeal diphtheria often presents with hoarseness and cough. The larynx may be the only site of infection (laryngoscopy will demonstrate a laryngeal pseudomembrane) or may be part of a continuum of respiratory tract involvement.

●Tracheobronchial infection usually develops secondary to membrane spread and may result in respiratory compromise, especially in children who have small airways.

C. diphtheriae may be cultured from mucous membranes or skin from asymptomatic carriers, who are an important reservoir for the organism in endemic areas.

Systemic manifestations — Absorption and dissemination of diphtheria toxin can lead to toxin damage of the heart (myocarditis), nervous system, and kidneys. In one retrospective study of 676 patients hospitalized with diphtheria in the Kyrgyz Republic, 30 percent had severe forms including 22 percent with myocarditis; 28 percent had exclusively tonsillar disease [4]. A report from Finland noted a 28 percent incidence of cardiac involvement [5].

The risk of developing cardiac and/or neurologic toxicity is proportional to the severity of local infection. Myocarditis (as evidenced by electrocardiographic changes such as ST-T wave changes, QTc prolongation, and/or first-degree heart block) can be detected in up to two-thirds of cases. The onset typically begins as local respiratory symptoms are improving [5,6].

Clinically evident cardiac dysfunction (decreased heart sounds, gallop rhythm, cardiac dilatation, dyspnea) occurs in 10 to 25 percent of patients with diphtheria [7]. Severe myocarditis is manifested by complex heart blocks and arrhythmias, heart failure, and circulatory collapse. Patients should be monitored with serial electrocardiograms and measurements of cardiac enzymes that reflect the intensity of myocardial damage. Cardiac complications are a major cause of mortality [8]. (See 'Prognosis' below.)

The time course for onset of myocarditis is variable; it typically occurs 7 to 14 days after the onset of respiratory symptoms. In one cohort, severe pseudomembrane and the "bull neck" of diphtheria preceded cardiomyopathy with positive predictive value of approximately 80 percent [9]. The presence of myocarditis is a poor prognostic factor; in one cohort of children in India, it was the strongest predictor of mortality [8].

Neurologic toxicity occurs in approximately 5 percent of patients [4]. Neurological toxicity is unusual in patients with mild disease, but it may develop in up to 75 percent of patients with severe diphtheria. Local neuropathies (paralysis of the soft palate and posterior pharyngeal wall manifested as nasal speech) are frequent and can be followed by cranial neuropathies (usually oculomotor and ciliary, followed by facial or laryngeal paralyses) [10]. Peripheral neuritis develops weeks to months later and can span the clinical spectrum from mild weakness to total paralysis. The severity of disease also correlates with the severity of membrane formation (and therefore toxin production), as well as the time between the onset of symptoms and administration of antitoxin [10,11]. (See 'Antitoxin' below.)

Renal failure from direct toxin activity or hypotension may occur in severe cases [12].

Non-toxigenic C. diphtheriae strains have been implicated in cases of endocarditis, mycotic aneurysms, osteomyelitis, and septic arthritis [13-15].

Cutaneous diphtheria — Cutaneous diphtheria is more common in topical areas and can be caused by toxigenic and non-toxigenic strains of C. diphtheriae, though systemic toxicity is rare. Cutaneous diphtheria is characterized by chronic, nonhealing sores or shallow ulcers with a dirty gray membrane; its appearance is fairly nonspecific (picture 3 and picture 4) [16]. Cutaneous diphtheria can also present in the form of colonization and infection of preexisting dermatoses [17]. The diagnosis is made by culturing the organism from a skin lesion. Local trauma frequently precedes cutaneous infection. Previous outbreaks of cutaneous disease have occurred in impoverished populations with poor access to the health care system, such as people experiencing homelessness and persons who inject drugs [18]. Skin infections typically result in a brisk antibody response, in contrast to pharyngeal infections (which may not result in subsequent immunity). Therefore, individuals with skin infection have a relatively low likelihood of developing the pharyngeal form of the disease; however, skin ulcers serve as a reservoir to infect susceptible hosts, particularly in regions where herd immunity is low due to suboptimal vaccination [19-22].

Outbreaks of cutaneous diphtheria in the United States have been described among men with alcohol use disorders who experience homelessness and other impoverished groups [23,24]. However, since 1980, the Centers for Disease Control and Prevention (CDC) has dropped cutaneous diphtheria caused by non-toxigenic strains from its list of reportable diseases. More detailed information on the epidemiology of diphtheria is presented in a separate topic review. (See "Epidemiology and pathophysiology of diphtheria".)

DIAGNOSIS

Approach to diagnosis — The diagnosis of diphtheria should be considered in the setting of relevant clinical manifestations (sore throat, malaise, cervical lymphadenopathy, and low-grade fever) together with appropriate epidemiologic risk factors, especially travel to endemic areas such as Africa, Latin America, Asia, the Middle East, and parts of Europe where immunization is suboptimal. Clinicians should also maintain an appropriately high index of suspicion for diphtheria among migrant and displaced populations who may be suffering from lack of access to health care and vaccination, as well as exposure to conditions that facilitate spread of the disease. (See "Epidemiology and pathophysiology of diphtheria".)

Mild pharyngeal erythema typically progresses to areas of white exudate; these coalesce to form an adherent gray pseudomembrane that bleeds with scraping. Clinical suspicion for diphtheria should be further heightened in the setting of adherent pharyngeal, palatal, or nasal membranes, systemic toxicity, hoarseness, stridor, palatal paralysis, and/or serosanguineous nasal discharge [25]. (See 'Clinical manifestations' above.)

Definitive diagnosis of diphtheria requires culture of C. diphtheriae from respiratory tract secretions or cutaneous lesions and a positive toxin assay. Routine laboratory results are usually nonspecific and may include a moderately elevated white blood cell count and proteinuria. (See 'Diagnostic tests' below.)

Definitive cases of diphtheria in the United States should be reported immediately to the state health department and the Centers for Disease Control and Prevention (CDC), and culture material should be sent to the CDC for confirmation. The CDC Pertussis and Diphtheria Laboratory offers culture, toxigenicity testing, polymerase chain reaction (PCR), and serology. For detailed information on specimen collection and shipping and to arrange PCR testing, the laboratory can be contacted by phone (404-639-1231) or fax (404-639-4421). In other countries, reports should be submitted to the World Health Organization (WHO).

Diagnostic tests

Culture — Cultures should be obtained from the throat and nares or any mucosal or cutaneous lesion that manifests characteristics similar to those discussed above. (See 'Clinical manifestations' above.)

Material for culture should be obtained from a portion of the membrane (if possible) and from beneath the membrane [26]. Multiple respiratory samples increase the yield of culture. Special culture media (Loffler's or Tindale's) is required; the microbiology laboratory should be notified of the suspected diagnosis so that the specimen is plated on appropriate media. Transport to the laboratory must be accomplished quickly since the media must be inoculated promptly [26]. In the United States, each specimen should be submitted with a completed DASH form [27].

A presumptive diagnosis of C. diphtheriae can be made by identifying gram-positive rods in a "Chinese character" distribution on Gram stain, black colonies with halos on Tindale's media, and metachromatic granules on Loffler's media (picture 5) [28].

Once the organism is presumptively identified, biochemical testing can be performed to confirm C. diphtheriae; it is catalase positive, urease negative, cystinase positive, and pyrazinamidase negative [29,30].

Toxin detection — Testing for toxin production must be performed to differentiate toxigenic from non-toxigenic strains of C. diphtheriae. If clinical suspicion for diphtheria is high, antitoxin should be administered promptly prior to confirmation of toxin production, which may take several days depending upon the method used.

Toxin production can be demonstrated by an in vitro assay that detects development of an immunoprecipitin band on antitoxin-impregnated filter paper laid over an agar culture of the organism (Elek test) [31]. The test requires quality control of reagents and a standardized procedure so is best performed in a reference laboratory [29]. In the United States, the CDC's Pertussis and Diphtheria Laboratory is the only laboratory that performs the Elek test [32].

PCR testing for the A subunit of the diphtheria toxin gene can be performed [31]. A positive PCR for the diphtheria toxin gene demonstrates the presence of the gene but does not indicate whether toxin is being produced; therefore, positive PCR results must be confirmed by culture to establish the presence of clinical disease due to a toxigenic strain of C. diphtheriae [29]. A negative PCR is helpful in excluding the diagnosis of diphtheria. PCR can be performed on colonies extracted from a plate or on clinical specimens. One group reported successful PCR testing on a formalin-fixed throat swab, which would not be suitable for culturing [33].

A rapid enzyme immunoassay (EIA) for the detection of diphtheria toxin production has been developed [34]. In a study of 245 mixed strains of Corynebacterium, comparable results were observed with EIA and Elek, though EIA testing was faster (3 versus 24 hours) [34].

Other tests, including matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF), may identify C. diphtheriae. However, when used alone, these tests do not confirm toxin production and are considered supplemental.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of respiratory diphtheria includes (table 1):

●Infectious mononucleosis – Clinical manifestations of infectious mononucleosis include fever, pharyngitis, adenopathy, and fatigue. Laboratory findings include atypical lymphocytosis; the diagnosis is established based on the presence of heterophile antibodies. (See "Infectious mononucleosis".)

●Group A streptococcal tonsillopharyngitis – Clinical manifestations of streptococcal pharyngitis include presence of tonsillar exudates, tender anterior cervical adenopathy, history of fever, and absence of cough. The diagnosis is established via a rapid antigen detection test or culture.

●Epiglottitis – Clinical manifestations of epiglottitis include fever, sore throat, dysphagia, drooling, and respiratory distress. The diagnosis is made by visualization of the epiglottis or demonstration of epiglottal swelling on lateral neck radiograph. (See "Epiglottitis (supraglottitis): Clinical features and diagnosis".)

●Viral pharyngitis – Viral infection is the most common cause of pharyngitis; etiologies include influenza, rhinovirus, respiratory syncytial virus, herpes simplex virus, human immunodeficiency virus (HIV), and others. (See "Evaluation of acute pharyngitis in adults", section on 'Respiratory viruses, including SARS-CoV-2'.)

●Vincent's angina – Vincent's angina (also called acute necrotizing ulcerative gingivitis) is an infection of the gums with sudden onset of painful, bleeding gums, blunting of interdental papillae, and an ulcerative necrotic slough of the gingiva. (See "Overview of gingivitis and periodontitis in adults", section on 'Necrotizing periodontal disease'.)

●Oral candidiasis – Clinical manifestations of oral candidiasis consist of white plaques on the buccal mucosa, palate, tongue or oropharynx. Patients may have loss of taste and pain with eating or swallowing. The diagnosis is confirmed by visualization of budding yeast on a Gram stain or potassium hydroxide preparation. (See "Overview of Candida infections", section on 'Oropharyngeal candidiasis'.)

●Corynebacterium ulcerans infection – C. ulcerans is primarily an animal pathogen but has the potential to elaborate diphtheria toxin and cause an exudative pharyngitis in humans that is indistinguishable from C. diphtheriae [35].

●Corynebacterium hemolyticum infection – C. hemolyticum is associated with pharyngitis, sometimes accompanied by a maculopapular or scarlatiniform rash. Membranous pharyngitis mimicking diphtheria caused by C. hemolyticum has also been described [36]. Other clinical manifestations include peritonsillar abscess and endocarditis.

INFECTION CONTROL PRECAUTIONS — Patients with diphtheria should be placed on respiratory droplet isolation for respiratory tract disease and contact precautions for cutaneous disease. Isolation should be continued until treatment has been completed and two consecutive cultures taken at least 24 hours apart are negative [37]. (See 'Follow-up' below.)

TREATMENT

Approach to treatment — The approach to treatment depends upon the clinical syndrome:

●Respiratory diphtheria – Respiratory diphtheria has case-fatality rates ranging between 5 and 10 percent [32]. Before treatment was available, the case-fatality rate was approximately 50 percent [38]. (See 'Prognosis' below.)

Patients with respiratory diphtheria can quickly develop severe disease. Thus, the decision to initiate treatment should be based on clinical presentation, travel history, and vaccination status pending the culture results. (See 'Approach to diagnosis' above.)

The treatment of respiratory diphtheria consists of antibiotic therapy and diphtheria antitoxin for severe cases. (See 'Antitoxin' below and 'Antibiotics' below.)

Careful airway management is also important due to risk of airway obstruction. (See 'Airway management' below.)

●Cutaneous diphtheria – The treatment of cutaneous diphtheria consists of antibiotic therapy; antitoxin is not usually needed given lack of pseudomembranes or cardiac involvement. (See 'Antibiotics' below.)

Antitoxin — Diphtheria antitoxin (DAT) is a hyperimmune antiserum produced in horses that binds to and inactivates the diphtheria toxin. Antitoxin was first shown to reduce mortality from 7 to 2.5 percent in a controlled trial published in 1898 [39].

The dose of antitoxin depends upon the site and severity of infection. Detailed information on dosing of diphtheria antitoxin can be found in the drug information topic within UpToDate.

Antitoxin is only effective before toxin enters the cell and therefore must be administered early [28]. Antitoxin is not commercially available in the United States but may be obtained from the Centers for Disease Control and Prevention (CDC); the CDC also provides telephone consultation for diagnosis and treatment questions. United States physicians can contact the CDC's Emergency Operations Center at 770-488-7100 (or at www.cdc.gov/diphtheria/dat.html) after consulting with their state health department. DAT is available from CDC under an investigational new drug (IND) protocol.

There is an approximately 10 percent risk of hypersensitivity and/or serum sickness. Before intravenous administration of antitoxin, tests for sensitivity to horse serum should be performed according to instructions provided with the material [37]. Epinephrine should be immediately available because of the potential for anaphylaxis. (See "Serum sickness and serum sickness-like reactions".)

Antibiotics — Antibiotic therapy should be started as soon as possible without waiting for diagnostic confirmation. Although it is not a substitute for antitoxin, it kills the organism and prevents further toxin production; it slows the spread of local infection; and it reduces the risk of transmission to others since people are usually no longer able to infect others 48 hours after they begin taking antibiotics.

●Regimen selection – For most patients, we administer penicillin or erythromycin [40-42]. Some studies suggest that erythromycin may be superior to penicillin in eradicating the carrier state [42]. However, data supporting these agents are limited, and almost all clinical trials of antibiotic efficacy were performed when diphtheria was more widespread and antibiotic choices were limited.

Azithromycin is a reasonable alternative when used for treatment of less severe disease and prophylaxis. In vitro testing of C. diphtheriae strains show low MICs for macrolides as a class [43,44], although trials evaluating clinical efficacy are lacking. In some guidelines, azithromycin is considered a first line agent [45].

C diphtheriae is usually susceptible to multiple other agents in vitro, including clindamycin, rifampin, quinolones, tetracyclines, trimethoprim-sulfamethoxazole, vancomycin, daptomycin, linezolid, and others [43,46]. Antibiotic susceptibility testing should be reviewed if there is resistance to penicillin or macrolides and one of these agents is being considered.

●Dosing and duration – Oral antibiotics are preferred if the patient can swallow; however, patients generally require initial parenteral therapy, which is then followed by oral therapy to complete a 14-day course.

Intravenous (IV) erythromycin is challenging to administer due to the potential for phlebitis at the site of administration and GI distress (eg, abdominal pain, diarrhea) secondary to strong gastric antral contractions induced by erythromycin. Penicillin or azithromycin are better tolerated intravenously.

Antibiotic dosing is as follows:

•Adults

-Erythromycin – The dose is 500 mg IV or orally four times daily for 14 days.

-Penicillin – Penicillin can be used parenterally either IV or intramuscularly (IM). The dose of aqueous penicillin G is 25,000 units/kg (maximum 1 million units/dose) IV every 6 hours [47]. The dose of penicillin G procaine is 1.2 million units IM every 24 hours [48]. The oral dose of penicillin V (phenoxymethylpenicillin) is 500 mg four times daily [40,41,49-51].

-Azithromycin – The dose for both IV and oral is 500 mg daily.

•Pediatrics

-Erythromycin – The dose is 40 to 50 mg/kg/day (maximum 2 g/day) IV or orally in four divided doses. IV erythromycin should be administered over at least 60 minutes to potentially prevent cardiac arrhythmias.

-Penicillin – The dose of aqueous penicillin G is 100,000 to 300,000 units/kg/day IV divided every six hours (maximum 1 million units/dose). Penicillin G procaine is given IM at a dose of 50,000 units/kg/day once daily or in two divided doses (maximum 1.2 million units/day). The oral dose of penicillin V (phenoxymethylpenicillin) is 10 to 15 mg/kg/dose (maximum 500 mg/dose) four times daily [37].

-Azithromycin – The dose is 10 to 12 mg/kg once daily (maximum 500 daily) for both IV and oral.

Airway management — Respiratory failure due to airway compromise is a major complication of diphtheria and is an important cause of mortality. In severely ill patients with signs of extensive pseudomembrane formation, stridor, or the toxic "bull neck" of diphtheria, respiratory failure should be anticipated and managed aggressively. Intubation may help to protect the airway, although frequently this is a difficult procedure in patients with diphtheria due to extensive airway edema and mucosal friability; there is also potential for inadvertent dislodging of the pseudomembrane. Ideally, intubation should be performed by experienced providers in the setting of operative backup for tracheostomy for definitive airway management [9].

Additional monitoring — Patients with respiratory diphtheria should be monitored with serial electrocardiograms and measurements of cardiac enzymes to reflect the intensity of myocardial damage. Neurologic status should also be monitored carefully. (See 'Follow-up' below.)

FOLLOW-UP

Duration of infection control precautions — For patients with respiratory infection, droplet precautions should be continued until the patient has completed the antibiotic course and is culture-negative on two consecutive cultures from the nose and throat taken 24 hours apart, with the first specimen collected 24 hours after therapy is completed [37,52].

For patients with cutaneous disease, contact precautions are recommended until elimination of the organism is documented by obtaining two consecutive negative cultures of the skin lesions 24 hours apart, with the first specimen collected 24 hours after therapy is completed [37,52].

If clearance does not occur, then an additional course of antibiotics is warranted [53]. Such patients should be managed in conjunction with an infectious diseases expert.

Immunization — Patients should receive diphtheria toxoid immunization during their convalescence since natural infection does not induce immunity.

MANAGEMENT OF CONTACTS — Close contacts include household members and other persons with a history of direct contact with a case-patient (eg, caretakers, relatives, or friends who regularly visit the home or share kitchen facilities) as well as medical staff exposed to oral or respiratory secretions of a case-patient.

●Once close contacts are identified, they should have nasal and pharyngeal cultures obtained (algorithm 1) [25].

●Contacts should be treated with antimicrobial therapy.

•Treatment typically consists of a 7 to 10 day course of oral erythromycin (for adults: 250 mg four times daily; for children 40 to 50 mg/kg/day [maximum 1 g/day] in three to four divided doses).

•If the individual is intolerant to erythromycin or compliance is a concern, a single dose of penicillin G benzathine (600,000 units intramuscularly [IM] for children <30 kg; 1.2 million units IM for individuals ≥30 kg) can be employed.

●If immunizations are not current, diphtheria toxoid immunization should be administered. (See "Tetanus-diphtheria toxoid vaccination in adults" and "Diphtheria, tetanus, and pertussis immunization in children 6 weeks through 6 years of age", section on 'Schedules' and "Diphtheria, tetanus, and pertussis immunization in children 7 through 18 years of age", section on 'Indications'.)

All contacts who test positive should be isolated (algorithm 1). After completion of therapy, follow-up cultures should be performed; if the cultures are positive, an additional 10-day course of erythromycin should be given, and pharyngeal specimens should be sent for additional cultures [37].

Contact tracing and management of close contacts should be done in conjunction with public health officials. In the United States, detailed information can be found on the CDC website.

PROGNOSIS — Diphtheria is a serious disease with case-fatality rates typically ranging between 5 and 10 percent [32]. Before treatment was available, the case-fatality rate was approximately 50 percent [38].

The case – fatality rates can vary depending upon the geographic location, the specific population, and the availability of resources. Among 676 hospitalized patients with diphtheria in the Kyrgyz Republic, the overall mortality was 2.8 percent [4]. Of the 19 patients who died, 79 percent presented to the hospital ≥4 days after onset of symptoms. The mortality rate was higher among the 151 patients with myocarditis than among those without myocarditis (7 versus 2 percent). In addition, the mortality rate was higher in patients <15 years of age than patients ≥15 years of age (5.5 versus 1.7 percent). Higher case-fatality rates, averaging about 20 percent, have been reported from Haiti [54].

SUMMARY AND RECOMMENDATIONS

●Causative agents – Respiratory diphtheria is typically caused by toxin-producing strains of C. diphtheriae; rarely, it is caused by toxigenic strains of other Corynebacterium species (C. ulcerans, C. hemolyticum, or C. pseudotuberculosis). Cutaneous diphtheria, which is more common in tropical areas, can be caused by toxigenic and nontoxigenic strains of C. diphtheriae.

●Clinical manifestations

•Respiratory diphtheria – Symptoms of respiratory diphtheria typically begin two to five days after infection. The most common presenting findings are sore throat, malaise, cervical lymphadenopathy, and low-grade fever. (See 'Respiratory diphtheria' above.)

In at least one-third of cases, local elaboration of toxin induces the formation of a coalescing pseudomembrane (composed of necrotic fibrin, leukocytes, erythrocytes, epithelial cells, and organisms). This membrane can extend to any portion of the respiratory tract from the nasal passages to the tracheobronchial tree. Up to two-thirds of cases have tonsillopharyngeal involvement; involvement of the laryngeal, nasal, and tracheobronchial areas is less common. (See 'Respiratory diphtheria' above.)

The diphtheritic membrane is classically gray in color and adheres tightly to the underlying tissue, such that dislodgement results in bleeding (picture 1 and picture 2). Systemic toxicity increases as the pseudomembrane spreads from the tonsillopharyngeal area. Absorption and dissemination of diphtheria toxin can lead to toxin damage of the heart and nervous system. Clinically evident cardiac dysfunction occurs in about 10 to 25 percent of patients; neurologic toxicity occurs in approximately 5 percent of patients. (See 'Systemic manifestations' above.)

•Cutaneous diphtheria – Cutaneous diphtheria is characterized by chronic, nonhealing sores or shallow ulcers with a dirty gray membrane. Cutaneous diphtheria can also present in the form of colonization and infection of pre-existing dermatoses. Systemic toxicity is rare. (See 'Cutaneous diphtheria' above.)

●Diagnosis

•Approach to diagnosis – The diagnosis of diphtheria should be considered in the setting of relevant clinical manifestations (eg, sore throat, malaise, cervical lymphadenopathy, and low-grade fever) together with appropriate epidemiologic risk factors. (See 'Approach to diagnosis' above.)

A definitive diagnosis of diphtheria requires culture of C. diphtheriae (from respiratory tract secretions or cutaneous lesions) and a positive toxin assay. (See 'Diagnostic tests' above.)

•Diagnostic testing – Cultures should be obtained from the throat and nose, including a portion of the membrane (if possible) and material from beneath the membrane. Special culture media are required; the microbiology laboratory should be notified of the suspected diagnosis so that the specimen is plated on appropriate media. (See 'Culture' above.)

Testing for toxin production must be performed to differentiate toxigenic from nontoxigenic strains of C. diphtheriae. This testing may take several days depending upon the method used. (See 'Toxin detection' above.)

●Infection control precautions – Patients with respiratory diphtheria should be placed on respiratory droplet isolation for respiratory tract disease and contact precautions for cutaneous disease. Isolation should be continued until two consecutive cultures taken at least 24 hours apart are negative. (See 'Approach to treatment' above.)

●Treatment

•Respiratory disease – The treatment of respiratory diphtheria consists of antibiotic therapy (erythromycin or penicillin and possibly azithromycin) and diphtheria antitoxin; the dosing and duration is outlined above. If clinical suspicion for diphtheria is high, antibiotic therapy and antitoxin should be started as soon as possible without waiting for diagnostic confirmation. (See 'Antitoxin' above and 'Antibiotics' above.)

Antitoxin can induce serum sickness; precautions include testing for sensitivity to horse serum and having epinephrine immediately available in case of anaphylaxis. (See 'Antitoxin' above.)

•Cutaneous disease – The treatment of cutaneous diphtheria consists of antibiotic therapy; antitoxin is not usually needed given lack of pseudomembranes or cardiac involvement. (See 'Antibiotics' above.)

●Airway management and monitoring – In patients with respiratory diphtheria, careful airway management is important due to risk of airway obstruction. (See 'Airway management' above.)

In addition, patients should be monitored with serial electrocardiograms and measurements of cardiac enzymes that reflect the intensity of myocardial damage. Neurologic status should also be monitored carefully. (See 'Approach to treatment' above.)

●Follow up – Isolation should be continued until treatment is completed and two consecutive cultures taken at least 24 hours apart are negative, with the first specimen collected 24 hours after therapy is completed. (See 'Follow-up' above.)

If clearance does not occur, then an additional course of antibiotics is warranted. Such patients should be managed in conjunction with an infectious diseases expert.

Patients should receive diphtheria toxoid immunization during their convalescence, since natural infection does not induce immunity.

●Management of contacts – Close contacts need to be identified, cultured, and considered for antimicrobial prophylaxis (algorithm 1). (See 'Management of contacts' above.)