Approach
The diagnosis of diphtheria is established by a combination of history, physical exam, and positive cultures from throat swabs, or other suspect lesions, for Corynebacterium diphtheriae. Polymerase chain reaction (PCR) testing can provide supporting evidence for the diagnosis of diphtheria and help to discriminate between toxigenic and nontoxigenic strains. The Elek test is a phenotypic test of toxin production.[39][40][41]
History
In respiratory diphtheria, symptoms typically begin with a sore throat and fever. As the disease progresses, dysphagia, dysphonia, dyspnea, and a croupy cough can develop, which signal pharyngeal and laryngeal extension of the pseudomembrane and/or neurologic involvement of the posterior pharyngeal and laryngeal nerves.[13][28] The risk of death from respiratory compromise and aspiration increases significantly when this occurs.
Obtaining a thorough history of previous immunizations, including diphtheria vaccination, is vital. Where possible, also obtain an immunization history from close contacts. A history of travel and/or exposure to sick individuals should also be sought.
Diphtheria remains endemic in Haiti and the Dominican Republic, and many countries in Asia, the South Pacific, and the Middle East.[12]
In cutaneous diphtheria, a history of underlying skin dermatoses in the setting of residential crowding or homelessness is typical. Cutaneous diphtheria should also be considered in travelers with wound infections who have arrived from countries where infection is endemic.[31] Initially, infected skin lesions tend to be shallow, painful, tender, and erythematous; by the time of presentation they are often ulcerated. Skin lesions tend to form on the extremities as these parts of the body have the greatest risk of acquiring cuts and abrasions, which then become secondarily infected with C diphtheriae.
Physical exam
If the upper respiratory tract is involved, a typical brown-grayish pseudomembrane begins to form over the tonsils and/or pharynx after 2 to 5 days of sore throat. It will typically bleed after attempts to remove or dislodge it.[12] Without prompt treatment, this pseudomembrane can thicken and spread to involve other parts of the oropharynx, nasopharynx, larynx, and trachea. Swelling of the neck and lymphadenopathy lead to a characteristic bull-neck appearance.
In cutaneous diphtheria, sharply defined, painful lesions that frequently ulcerate and are covered by a brownish-gray membrane may be noted.[2][13][Figure caption and citation for the preceding image starts]: A typical pseudomembrane in a diphtheria patientPublic Health Image Library (PHIL), CDC [Citation ends].
[Figure caption and citation for the preceding image starts]: Corynebacterium diphtheriae taken from an 18-hour culture, using Albert stainPublic Health Image Library (PHIL), CDC [Citation ends].
[Figure caption and citation for the preceding image starts]: Cutaneous diphtheria: note the deep ulcer with well-defined marginsPublic Health Image Library (PHIL), CDC [Citation ends].
[Figure caption and citation for the preceding image starts]: Skin lesion caused by the Corynebacterium diphtheriaePublic Health Image Library (PHIL), CDC [Citation ends].
Laboratory testing
The diagnosis of diphtheria requires confirmation by microbiologic culture and microscopy. This requires the use of blood agar and a blood agar medium containing tellurite (Hoyle), or Tinsdale media.[41] Nose and throat swabs are taken for culture or molecular testing in suspected respiratory diphtheria patients and their close contacts. Where possible, swabs should be taken from beneath the pseudomembrane, taking care not to dislodge it, exacerbate respiratory obstruction, or cause it to bleed.
Culture distinguishes C diphtheriae from other Corynebacterium species that are part of the natural flora of the nasopharynx and skin (e.g., diphtheroids).[39] Even if the patient's culture is negative, isolation of C diphtheriae from close contacts may enable confirmation of the diagnosis.[1]
A modified Elek test is the gold standard to determine the toxigenicity of isolated C diphtheriae strains, but this is a technically difficult test and is not always available, particularly in outbreak settings.[39][41] In the US, the Centers for Disease Control and Prevention (CDC) has the only laboratory able to perform Elek testing.[12] PCR is therefore often useful as an initial toxigenicity test. PCR testing can help to discriminate between toxigenic and nontoxigenic strains by detecting genes associated with the diphtheria toxin (dtxR and tox).[39][40][41] It discriminates toxigenic from nontoxigenic bacteria in most cases, though it is important to remember that nontoxigenic toxin gene bearing strains of C diphtheriae occasionally occur.[41] As culture-based isolation of C diphtheriae is often unsuccessful once antibiotic treatment has been initiated, PCR can also be useful because it still identifies non-viable C diphtheriae organisms from clinical specimens.
Diphtheria antibody levels can also be measured. If levels are high, the disease is less likely to produce a severe illness. However, serology is infrequently available and of limited utility; it is not useful after antitoxin has been administered. If antibody titers are low (a nonprotective diphtheria antibody titer is <0.01 IU/mL), a diagnosis of diphtheria cannot be excluded.[39][41]
Reporting
In the US, suspected diphtheria cases should be reported promptly by telephone to the CDC so that diphtheria antitoxin can be obtained; this is the only source of antitoxin within the US.[1] The state health department should also be contacted to ensure state-specific reporting requirements are met.
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