Essentials of Diagnosis

  • Tender papule develops into a pustule after an incubation period of 4–7 days; the pustule ruptures within a few days to produce a nonindurated, painful ulcer with a purulent base and undermined or ragged borders.
  • Unilateral tender inguinal adenopathy may progress to a bubo (fluctuant lymph node mass) that spontaneously ruptures or requires drainage.
  • Isolation of the causative organism, Haemophilus ducreyi, by special culture media.

General Considerations

Chancroid is a sexually transmitted genital ulcer disease caused by Haemophilus ducreyi, a small, fastidious, gram-negative rod. Worldwide, chancroid incidence exceeds that of syphilis in many developing countries. In 1997, the World Health Organization estimated that there were six million new cases of chancroid. Based on polymerase chain reaction (PCR) assays, chancroid prevalence has been shown to range from 23% to 56% in endemic areas (Africa, Asia, and the Caribbean). In the United States and western Europe outbreaks are episodic. The infection is also up to 25 times more prevalent in men than in women, a difference recognized in both naturally occurring and experimental disease in humans and macaques. In fact, although controversial, it has been suggested that women may be asymptomatic carriers or reservoirs of the infection.

Although chancroid is uncommon in North America, outbreaks occur in the inner cities of the United States. The most recent of these began in the late 1980s in an outbreak attributed to sexual behavior associated with crack cocaine use and sex in exchange for drugs or money. The number of cases peaked in 1988, when 5001 cases were reported. Since then, the number of cases has sharply declined to an all-time low of 30 cases reported in 2004. Currently chancroid is rare in the United States and Canada.

The reasons for the decline in reported chancroid cases are multifactorial and not completely understood. There did not appear to have been a decline in sexual risk behavior or crack cocaine use in the at-risk populations. Improved provider education and awareness, condom promotion, partner notification and treatment programs, and the addition of chancroid treatment to the syndromic management of genital ulcers all may have played a role. Previous localized chancroid outbreaks appear to have been controlled by identifying and treating reservoir core groups such as commercial sex workers.

A major constraint to understanding chancroid epidemiology has been the lack of sensitive and specific diagnostic tests. The organism is fastidious and difficult to culture. When diagnosis is based on clinical criteria alone, the infection is likely to be grossly over-reported in some circumstances and under-reported in others. The development of sensitive and specific PCR assays for H. ducreyi, it is hoped, will correct the problem of misdiagnosis in the future.

Chancroid has been shown to facilitate HIV transmission by providing both a portal of entry and an exit for the virus. In other words, chancroid increases both the transmissibility and the susceptibility of HIV and may do so by two mechanisms. First, increased viral shedding occurs in the ulcer exudates in HIV-infected patients with chancroid, thus making the virus available for transmission during sexual intercourse. Studies have shown that the mere presence of lesions does not always prevent chancroid patients from having sex. Second, recruitment of CD4 cells, the primary targets of the virus, to chancroidal ulcers serves to increase susceptibility of HIV-infected individuals to HIV acquisition. Finally, there are challenges in chancroid treatment among HIV coinfected patients as prolonged duration of ulceration and more frequent treatment failures have been reported.

Pathogenesis

H. ducreyi enters the skin through microabrasions that occur during sexual intercourse. A local tissue reaction leads to development of an erythematous papule that progresses to a pustule. The lesion then undergoes central necrosis to ulcerate. Histologic evaluation of these lesions reveals a deep necrotic ulcer surrounded by an infiltrate of neutrophils, macrophages, Langerhans cells, and CD4 and CD8 cells. Viable H. ducreyi are demonstrable in lesions, but very few organisms have been found within phagocytes. This finding, combined with a lack of interaction noted between the organisms and surrounding cells, suggests that H. ducreyi is primarily an extracellular organism with the ability to resist cellular uptake and phagocytosis through mechanisms that have not yet been completely elucidated.

H. ducreyi pathogenesis has been studied in tissue culture, animal models, and a human challenge model. Virulence factors identified include the presence of a pilus, lipooligosaccharide, a cytolethal distending toxin, a hemolysin, a hemoglobin-binding outer membrane protein, a copper-zinc superoxide dismutase, a zinc-binding periplasmic protein, and a filamentous hemagglutinin-like protein. These potential virulence factors and isogenic mutants of H. ducreyi developed to facilitate examination of these factors have been studied extensively in tissue culture, animal models, and human challenge models. H. ducreyi virulence is no doubt multifactorial, as is the case for many other organisms.

Prevention of chancroid

Prevention and control of chancroid is important for several reasons. Foremost among these is the association of chancroid with HIV transmission in parts of the world where both infections are endemic. Because chancroid lesions are often painful, patients often seek and receive treatment early, making it possible for partners to be notified and treated in a timely manner. Chancroid thrives in populations with high sexual activity, especially where many men are having sex with relatively fewer women, usually sex workers. If these factors can be reduced significantly, transmission will slow or even cease and chancroid prevalence will markedly diminish.

Successful chancroid control has been carried out in Thailand and other countries where multifaceted interventions have been implemented. Promotion of condom use, syndromic management of genital ulcers, treatment of patients who have reactive syphilis serology, contact tracing and treatment, education, and monthly presumptive treatment with azithromycin have contributed to reductions in chancroid and genital ulcer disease in Thailand and South Africa. Treatment of core groups in Canadian epidemics also has had a dramatic effect on the number of cases of chancroid.

Additional insights regarding chancroid prevention were provided by an H. ducreyi human challenge model in which azithromycin not only successfully treated infection, but also blocked experimental reinfections for up to 2 months. Based on these observations it is now thought that the success of the South African intervention trial may have been due not only to azithromycin treatment efficacy, but also to the drug’s prophylactic effect.

Clinical Findings

Symptoms and Signs

Chancroid begins as a papule that evolves into a pustule after an incubation period of 4–7 days. The pustule then erodes into the classic nonindurated, painful ulcer with a purulent base and ragged, undermined borders. The ulcers can be single or multiple and usually remain confined to the genital area. Vesicle formation is not a feature of chancroid. In some cases mild constitutional symptoms have been associated with infection.

In men ulcers are most likely to be found on the internal or external surface of the prepuce, coronal sulcus, or frenulum. The shaft of the penis, prepucial orifice, urethral meatus, and glans penis may also be involved. In women most lesions are found at the vaginal entrance, including the labia majora and minora, fourchette, vestibule, and clitoris. About 50% of male patients present with a single ulcer, but a study of women with chancroid reported a mean number of 4.5 discrete ulcers. Smaller ulcers may also coalesce or merge to form a single giant ulcer or serpiginous ulcers. Other clinical variants of chancroid have been recognized and are outlined in Table Clinical Variants of Chancroid. Ulcers have been rarely reported at extragenital sites such as the thighs, anus, breasts, hands, mouth, abdomen, and feet, but these lesions are secondary to local contact or autoinoculation and do not represent hematogenous dissemination from the primary genital lesion(s).

Table Clinical Variants of Chancroid

Variant Clinical Features
Dwarf chancroid Small, superficial, relatively painless ulcer
Giant chancroid Large granulomatous ulcer at the site of a ruptured inguinal bubo, extending beyond its margins
Follicular chancroid Seen in women in association with hair follicles of the labia majora and pubis; initial follicular pustule evolves into a classic ulcer at the site
Transient chancroid Superficial ulcers that may heal rapidly, followed by a typical inguinal bubo
Serpiginous chancroid Multiple ulcers that coalesce to form a serpiginous pattern
Mixed chancroid Nonindurated tender ulcers of chancroid appearing together with an indurated nontender ulcer of syphilis having an incubation period of 10–90 d
Phagedenic chancroid Ulceration that causes extensive destruction of genitalia following secondary or superinfection by anaerobes such as Fusobacterium spp or Bacteroides spp (Vincent organisms)
Chancroidal ulcer Most often a tender, nonindurated, single large ulcer caused by organisms other than Haemophilus ducreyi; lymphadenopathy is conspicuous by its absence

In HIV-infected patients multiple ulcers are more common, duration of ulceration is longer, and treatment failure is more often a problem. Interestingly, no cases of opportunistic, systemic, or disseminated chancroid have been reported in patients coinfected with HIV.

Unilateral tender inguinal lymphadenopathy is also a characteristic finding in up to 50% of patients with chancroid. This may progress to development of buboes or fluctuant lymph nodes, which can rupture spontaneously or require drainage. H. ducreyi has been isolated from pus removed from these buboes. Lymphadenitis and subsequent bubo formation have been noted less frequently in women.

Laboratory Findings

Laboratory diagnosis of chancroid depends on identification of H. ducreyi in genital ulcer secretions or bubo pus. Gram stain of these secretions can reveal gram-negative, pleomorphic coccobacilli in a “schools of fish,” “railroad,” or “fingerprint” pattern, but this test lacks both sensitivity and specificity. Stains are misleading due primarily to the polymicrobial contamination of the ulcer bases. Therefore, direct microscopy is not recommended for the routine diagnosis of chancroid.

For many years culture was considered the “gold standard” for chancroid diagnosis and for the evaluation of new diagnostic tests. Unfortunately, culture of H. ducreyi is difficult due to the fastidious nature of the organism. It is optimal for clinical samples to be plated directly onto special culture media in the clinic setting or be rapidly transported to the laboratory because there is no widely available, proven transport media. Even under ideal clinical conditions and with the cultures performed in highly experienced laboratories, the sensitivity of culture is still only about 75%.

PCR-based methods with improved sensitivity have been developed and now should probably be considered the new “gold standard” for H. ducreyi identification. A genital ulcer disease multiplex PCR assay (M-PCR), which simultaneously amplifies gene targets for H. ducreyi, Treponema pallidum, and herpes simplex virus types 1 and 2, is available for research purposes at the Centers for Disease Control and Prevention (CDC). Specimens can be transported to the laboratory and stored at –70xC for batch testing using this method. Unfortunately, PCR assays are not commercially available. However, they continue to be valuable tools for outbreak and epidemiologic investigations.

Antigen detection methods using monoclonal antibodies to detect H. ducreyi in ulcer secretions have been developed and are simple, rapid, sensitive, and inexpensive, but also not available commercially.

Serologic methods to detect antibody to H. ducreyi also have been described using both outer membrane protein and lipooligosaccharide. Although these methods are not able to distinguish recent from past infections, they provide useful screening tools for community-level epidemiologic studies.

Differential Diagnosis

Because definitive laboratory diagnosis of chancroid is rarely available in most clinical settings, health care providers must usually rely on clinical diagnosis. Unfortunately, the clinical diagnosis of chancroid based on physical examination alone has low sensitivity and specificity, even in the hands of experienced STD experts. Although the suggestive combination of painful ulcer and tender adenopathy occurs in 33% of patients, the accuracy is only 30–50% based solely on clinical features. The CDC recommends that a probable diagnosis of chancroid be made if the following criteria are present: (1) the patient has one or more painful ulcers; (2) the patient has no evidence of syphilis by darkfield examination of ulcer exudate or by serologic testing performed at least 7 days after onset of ulcers; (3) the clinical presentation, appearance of genital ulcers, and, if present, regional lymphadenopathy are typical for chancroid; and (4) the result of a test for herpes simplex virus performed on the ulcer exudate is negative.

Despite many distinguishing features, there is considerable overlap between the clinical appearance of chancroid, primary syphilis, and herpes simplex virus. Thus, these genital ulcer diseases are often confused with one another. Table Differential Diagnosis of Chancroid outlines the classic differences in clinical presentation of these three diseases.

Table Differential Diagnosis of Chancroid

Disease Characteristics of Lesion Other Clinical Findings
Chancroid Painful nonindurated ulcer with irregular undermined borders and a purulent exudative base Associated with tender, suppurative lymphadenopathy in up to 50% of patients
Primary syphilis Painless, clean-based, indurated ulcer or chancre  — a
Genital herpes Crops of small vesicles or blisters on an erythematous base that rapidly evolve into tiny, shallow ulcers; these may coalesce to form larger ulcers Fever in primary cases
Dysuria, urethritis, and (rarely) urinary retention

a Rash and other symptoms of secondary syphilis develop after resolution of the initial lesion.

The classic chancroid triad of painful ulcer, purulent base, and undermined edges occurs in less than 50% of patients. In addition, it is estimated that 10% of patients with chancroid are coinfected with syphilis or herpes. For this reason a syndromic approach to genital ulcer disease management — empirically treating prevalent infections — is recommended when both chancroid and syphilis are present in the community. The syndromic management approach results in patients receiving treatment for both chancroid and syphilis at the time of initial presentation. Although genital herpes is the most common cause of genital ulceration worldwide, empiric antiviral treatment for this disease is generally not recommended.

Complications

Some patients with bubo formation secondary to chancroid develop extensive adenitis and large inguinal abscesses. To avoid spontaneous rupture and a possible draining sinus or giant ulcer formation, buboes larger than 5 cm should be either aspirated or incised and drained. In the past it was thought that aspiration was preferable because of the potential for sinus tract formation subsequent to incision and drainage. This concern has not been substantiated. Although needle aspiration is an easier procedure, a recent study demonstrated that incision and drainage, when combined with appropriate antibiotic therapy, was an effective strategy and had the advantage of avoiding the need for frequent reaspiration.

Another complication of chancroid is development of superinfected ulcers due to organisms such as Fusobacterium, Bacteroides species, and other mixed aerobic and anaerobic flora. These ulcers may become very large and are extremely destructive to genital tissues. Such superinfected lesions may require debridement. In addition, these lesions and other large chancroid ulcers may result in disfiguring scars.

Phimosis, a late complication of chancroid, results from thickening and scarring of the foreskin and may require referral for therapeutic circumcision.

Treatment

Pharmacotherapy

Control of chancroid requires treatment of index cases and exposed partners with effective antibiotics (see Table Recommended Treatment Regimens for Chancroid). Although H. ducreyi has acquired resistance to several antibiotics through both plasmid- and chromosomally mediated mechanisms, several regimens are available for cure, resolution of clinical symptoms, and prophylaxis.

Table Recommended Treatment Regimens for Chancroid.a

Azithromycin, 1 g PO in a single dose
  or
Ceftriaxone, 250 mg IM in a single dose
  or
Ciprofloxacin, 500 mg PO twice daily for 3 d
  or
Erythromycin base, 500 mg PO 3 times daily for 7 d

a Ciprofloxacin is contraindicated in pregnant and lactating women. Azithromycin and ceftriaxone offer the advantage of single–dose therapy.

Plasmid-mediated resistance has been documented for sulfonamides, tetracyclines, penicillins, chloramphenicol, and aminoglycosides. Chromosomally mediated resistance is reported for penicillin, ciprofloxacin, ofloxacin, and trimethoprim. For many years, trimethoprim-sulfonamide regimens were the therapy of choice, but rapid and widespread resistance now precludes use of this combination. In addition, several isolates with intermediate resistance to ciprofloxacin and erythromycin have been reported, reminding clinicians of the need to maintain surveillance for H. ducreyi antibiotic susceptibility in endemic areas.

Follow-Up

Patients should be reexamined 3–7 days after initiation of treatment, at which time subjective improvement should occur. Objective improvement should be noted within 7 days. If there is no improvement several factors should be considered, including whether the diagnosis was correct, compliance with therapy, coinfection with another STD or HIV, and the possibility of antibiotic resistance. Resolution of symptoms also depends on ulcer size and whether or not patients are circumcised. Healing is slowed for ulcers located under the foreskin in uncircumcised men, and large ulcers may require 2 weeks or longer to heal. Slow clinical resolution of fluctuant lymphadenopathy can also be expected and usually requires needle aspiration or incision and drainage.

Patients coinfected with chancroid and HIV require special follow-up and monitoring because of the increased likelihood of treatment failure and slow-healing ulcers. HIV-infected patients require longer courses of therapy, and treatment failure can occur with any regimen. Of particular interest is the 30% failure rate of single-dose ceftriaxone reported in an African treatment trial. Because of this trial and limited data from other reports concerning the therapeutic efficacy of single-dose ceftriaxone and azithromycin regimens in HIV-infected patients, these regimens should be used only if close follow-up can be ensured. Some experts prefer to use the 7-day regimen of erythromycin in treating HIV-infected persons.

Follow-up should also be provided for all persons who have had sexual contact with chancroid patients during the 10 days preceding the onset of the patient’s symptoms. These partners should be examined and treated for chancroid regardless of whether symptoms of the disease are present.

It is also recommended that all chancroid patients be tested for HIV and syphilis at the time of diagnosis and 3 months later if initial test results were negative.

When to Refer to a Specialist

In the developed nations where chancroid is seldom seen, all patients suspected of having this disease should be referred to a clinician experienced in STD management. Such individuals generally know if there are local clinical or public health laboratories available with the expertise to identify the organism. State health departments can send properly collected ulcer swab specimens for H. ducreyi–specific PCR or M-PCR to the CDC’s reference laboratory for testing. The importance of such referrals is that if chancroid is documented to have been acquired domestically rather than in an endemic area of the world, it may represent the onset of a new chancroid epidemic with important public health implications, as previously discussed.

Prognosis

Effective antibiotic therapy exists for chancroid cure, resolution of clinical symptoms, and interruption of transmission. The prognosis is excellent in this regard, but because patients are capable of being reinfected, it is essential that sex partners be contacted and treated with effective therapy, even in the absence of symptoms.

Providers should also maintain heightened awareness of the potential for sporadic chancroid outbreaks as well as for development of antibiotic resistance in endemic settings. Finally, because of the association of chancroid with HIV transmission and the challenges of definitive diagnosis, it is critical that syndromic assessment and treatment of genital ulcers be implemented at the appropriate time and that patients receive treatment for both chancroid and syphilis when necessary.

Practice Points

  • Vesicle formation is not a feature of chancroid.
  • A syndromic approach to genital ulcer disease management — empirically treating prevalent infections — is recommended when both chancroid and syphilis are present in the community.

Relevant Web Sites

[Centers for Disease Control and Prevention case definition of chancroid:]

http://www.cdc.gov/epo/dphsi/casedef/chancroid_current.htm

[Sexually Transmitted Diseases Resource on chancroid:]

http://herpes-coldsores.com/std/chancroid.htm

[American Social Health Association patient information on chancroid:]

http://www.ashastd.org/learn/learn_chancroid.cfm

[CDC sexually transmitted diseases treatment guidelines 2006:]

http://www.cdc.gov/std/treatment

[CDC clinical slide file of STDs]

http://www2a.cdc.gov/stdclinic/

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