In the diagnosis of GUD, the first consideration is whether or
not the condition is sexually acquired; that is, whether a potential
sexual exposure has occurred. Thus, an accurate sexual history is
essential to diagnosis and management. Many clinicians may not readily
elicit a sexual history in busy clinical practices, and many patients
are unwilling to broach the subject of their sexual practices if
they are not fully comfortable with their health care provider.
Nevertheless, because accurate information about potential sexual
exposures is essential to a diagnosis, it is incumbent on any health
care provider who sees sexually active patients to become proficient
in this area of history taking. Details about obtaining an accurate
sexual history are found in Chapter 31.
Once a potential sexual route of infection has been established,
the history can sometimes help differentiate between different pathogens.
The interval between a high-risk sexual exposure and the onset of
symptoms may suggest the diagnosis. A primary genital herpes infection
most often produces symptoms within a week of exposure. Symptoms
of primary syphilis generally appear after 2–3 weeks, and
more uncommon pathogens may have a longer incubation period. The patient’s
description of the initial stages of the lesion (eg, as small blisters [vesicles])
may be helpful; however, these earlier stages may not have been
noticed by the patient, particularly if the lesions are in an area
that is difficult for the patient to inspect, such as the perineum,
labia majora or minora, or perianal region. In addition, patients
may not reliably distinguish an initial lesion as papular, vesicular,
or pustular; thus, the patient’s description is frequently
not contributory. A history of travel to an endemic area may increase
the likelihood of a more exotic pathogen, such as chancroid or donovanosis.
If sexually acquired GUD has been ruled out, a more detailed
history may be helpful in pointing toward certain less common diagnoses.
An appropriate exposure history in an endemic area, for example,
may suggest tularemia; likewise, a history of oral ulcers can suggest
Behçet syndrome, an uncommon disease of unknown etiology
whose hallmarks are recurrent oral and genital ulcers. However,
most of the nonvenereal causes of genital ulceration are less common
than sexually transmitted GUD. As a general rule, whenever there
is doubt as to the etiology, it is safest to assume that genital
ulcers are sexually acquired. Even a highly experienced provider
with expertise at obtaining an accurate sexual history will frequently
be given unreliable information about sexual risk.
Classic textbook descriptions would have the clinician believe that
herpes, syphilis, and chancroid can be easily distinguished on the
basis of physical presentation and symptoms. In fact, diagnosis of
specific etiologies of GUD on the basis of clinical presentation
alone is often impossible. Nevertheless, it is helpful to be familiar
with the “textbook” distinguishing characteristics,
which are summarized in Table 4–1. Important findings to
note include whether the ulcer is single or multiple, painless or
painful, tender or nontender, and indurated or soft. The base of
the ulcer may be necrotic (as in chancroid) or clean (as in a syphilitic
chancre); it may appear shallow or have raised or rolled margins.
The location of the ulcers also should be noted, because conditions
such as chancroid are most often confined to the prepuce and glans
in men and the labia majora and minora in women. Ulcers seen on
the scrotum in men or the cervix in women should raise suspicion
for herpes or syphilis.
Table 4–1. Characteristics of Genital Ulcers. ||Download (.pdf)
Table 4–1. Characteristics of Genital Ulcers.
|Disease||Incubation Period||Pain and Tenderness||Lymphadenopathy||Description|
|Genital herpes||2–7 d for primary infection, not applicable for recurrence||Present, along with tingling and itching||Bilateral and tender in primary infection||Clusters of small shallow ulcers that may coalesce; vesicles are often not seen in women|
|Syphilis||10–90 d; usually 2–3 wk||Painless, nontender||Bilateral, firm, nontender||Firm, cartilaginous induration; heaped-up margins; clean base with serous exudate|
|Chancroid||3–10 d||Painful in men; may be painless in women||Painful, tender, usually unilateral||“Soft chancre” (no induration); may be multiple, especially in women; ragged border; necrotic base that bleeds easily|
|Lymphogranuloma venereum||3–30 d||Varies, usually painless||Very tender, usually unilateral; most often the predominant finding in male penile disease; usually absent in vaginal or anal disease||Exquisitely tender adenopathy is predominant; ulcer is small (≤1 cm) and transient|
|Donovanosis (granuloma inguinale)||8–80 d||Painless||Absent; firm, subcutaneous granulomas (pseudobuboes) ||Hypertrophic, beefy red, or verrucous; may resemble squamous cell carcinoma or condylomata lata may be present|
The presence of inguinal lymphadenopathy can provide a clue to the
etiology of GUD. Enlarged inguinal lymph nodes are a common finding
in many ulcerating conditions. In primary genital herpes the enlarged
lymph nodes are frequently tender, whereas the classic adenopathy
of syphilis is firm and nontender. Less common diseases such as
chancroid and lymphogranuloma venereum usually present with tender,
fluctuant inguinal lymph nodes (buboes). In lymphogranuloma venereum
the primary ulcer may be transient, and lymphadenopathy, most often
unilateral, is the predominant finding. The lymph nodes in patients
with lymphogranuloma venereum become large and matted, and may erode
through the skin to produce draining sinus tracts. Donovanosis, described
in more detail below (see Differential Diagnosis), is one of the
few causes of genital ulcer disease that does not characteristically
include inguinal lymphadenopathy, although it can produce firm subcutaneous
swellings called pseudobuboes.
Physical examination should include a thorough inspection of the
oral cavity and a general skin examination. The presence of fever,
malaise, headaches, or other constitutional findings in conjunction
with a genital ulcer strongly suggests either primary genital herpes
or a nonvenereal systemic disease such as Behçet syndrome
or tularemia. In general, primary syphilis, chancroid, donovanosis,
and the ulcerative stage of lymphogranuloma venereum are not associated
with systemic symptoms. Rarely, a chancre will persist until the
onset of secondary syphilis.
Because clinical findings are not reliable for diagnosis of GUD,
the appropriate choice of diagnostic tests and collection of samples
is critical. Even in optimal circumstances, however, laboratory
testing may fail to produce a diagnosis. In fact, in research studies
of GUD, laboratory investigation fails to identify a pathogen in
up to one third of cases.
The most reliable way of diagnosing a syphilitic chancre at the
time of presentation is to identify live treponemes in a microscopic
examination of the ulcer exudate, using darkfield microscopy. The
organisms are abundant and have a characteristic appearance and
motility. Visualizing spirochetes from a genital ulcer is pathognomonic
for primary syphilis; darkfield examination of oral or intrarectal
ulcers must be interpreted with more caution, because they may be
contaminated by commensal spirochetes that are part of the resident
Although visual inspection using darkfield examination is a mainstay
of classic venereology, this test is no longer practical for most
clinicians, because accurate visual identification of treponemes requires
some experience, and most clinicians have not performed enough of
these examinations to be proficient. Additionally, most clinical
practices do not have access to darkfield microscopy.
Serologic testing for syphilis is the major method by which syphilis
is diagnosed and comprises a generally inexpensive nontreponemal
screening test (eg, rapid plasma reagin, RPR), with reactive tests
confirmed by a more specific treponemal assay, such as the fluorescent
treponemal antibody absorbed (FTA-ABS) or
particle agglutination (TP-PA) assay. Although highly sensitive
for syphilis in secondary and early latent disease, syphilis serologies
may be nonreactive in a large proportion of acute, primary infections.
Furthermore, previous syphilis infection can confound the diagnosis,
because positive findings on both the RPR and treponemal tests can
persist for long periods of time despite successful treatment. Finally,
syphilis may coexist with other causes of GUD; therefore, serologic testing
for syphilis should be performed in all patients presenting with
GUD, even if an alternative diagnosis is strongly suspected, unless
such testing has been done recently.
The measurement of changes in syphilis serologic responses is
helpful in differentiating recurrent from chronic infections. Individuals
in whom serial syphilis serologies do not decrease by at least fourfold
within 6 months after appropriate clinical treatment may be diagnosed
with recurrent infection, if the clinical history is corroborative.
In some individuals serologic responses remain reactive more than
6 months after successful antitreponemal therapy, a condition referred
to as “serofast.” These individuals are generally
at low risk for recurrent infection and may have other predisposing
conditions (eg, HIV infection or autoimmune diseases).
Serologic testing for type-specific HSV antibodies can be helpful
in supporting a diagnosis of genital herpes. However, because 30–40% of
genital herpes infections are caused by HSV-1, the absence of HSV-2
antibodies does not rule out such infections. Furthermore, although
the presence of HSV antibodies can support the diagnosis, it cannot
rule out other proximate causes or distinguish between active genital
herpes and prior history of genital herpes. HSV antibody testing
thus plays very little role in the etiologic diagnosis of GUD.
HSV-1 and HSV-2 are easily grown in cell culture, and with current
technology a presumptive positive culture can be read in as little
as 2 days. However, viral culture is of limited sensitivity in later
disease and is not likely to be positive after crusting or scabbing
of lesions has occurred. Nevertheless, given its ease of performance
and high positive predictive value, viral culture should be considered
a test of first choice for diagnosis of genital herpes, especially
in patients in whom the etiology is not obvious.
Nucleic Acid Amplification Tests
A PCR assay has been developed for the detection of HSV DNA from
a genital ulcer swab. This assay can be performed in real time,
with results often available within hours, and can distinguish HSV-1
from HSV-2. PCR is at least as sensitive as viral culture and is
clearly superior to culture later in the course of genital herpes
disease after lesions have ulcerated. Drawbacks of the test include
cost and availability; although most commercial laboratories perform
If an etiology has not been determined by other laboratory testing
and an ulcer has failed to respond to empiric antimicrobial therapy
directed against the most likely pathogens, a biopsy may be appropriate.
Besides identifying a causative agent, a biopsy of a nonhealing
ulcer should be pursued to rule out cancer. When donovanosis is
suspected, a crush preparation can be examined to look for the characteristic
Donovan bodies in cells from the ulcer base. For this purpose, a scraping,
curettage, or excisional biopsy specimen is crushed between two
glass slides, then air-dried and stained.
is fastidious and not easily grown in culture; however, a bacterial
culture using select media is still recommended if chancroid is
suspected, because isolation of
in culture establishes the diagnosis with certainty. Although antibiotic
resistance is not common in chancroid, bacterial culture also permits
confirmation of antimicrobial susceptibility. Nevertheless, a negative
culture should not be relied upon to exclude chancroid. Other bacterial
causes of GUD (syphilis, lymphogranuloma venereum, donovanosis)
are not routinely diagnosed by culture.
A swab of the exudative base of a suspected chancroid ulcer can
also be examined with Gram stain for the presence of typical gram-negative
coccobacilli. This test is also less useful for the practicing clinician
than might be hoped; Gram-negative bacilli of a variety of morphologies
may be seen from superficially colonized or secondarily infected
wounds, and the textbook “school of fish” arrangement
that is considered suggestive of chancroid on Gram stain requires
interpretation by a microscopist familiar with the disease.
A Tzanck preparation is a scraping from the base of a skin lesion,
smeared on a slide and stained with Giemsa or Wright stain. The
presence of multinucleated giant cells establishes the causative agent
as a herpesvirus. In real-world settings most clinical practices
are not set up for same-day preparation and interpretation of Tzanck
smears. In addition, the sensitivity of a Tzanck smear diminishes
considerably after vesicular lesions have ulcerated. For these reasons,
and with the availability of technologies such as shell vial culture
and PCR, which permit rapid diagnosis of genital herpes, the Tzanck
preparation has no role in the diagnosis of GUD.