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Dermatologic Manifestations of Chancroid

Author : Ivan D Camacho
Updated: Dec 6, 2012

Background
Chancroid is a sexually transmitted genital ulcer disease (GUD) caused by the gram-negative bacillus Haemophilus ducreyi. Chancroid is characterized by the presence of painful ulcers (see image below) and inflammatory inguinal adenopathy.

Chancroid usually starts as a small papule that rapidly becomes pustular and eventually ulcerates. The ulcer enlarges, develops ragged undermined borders, and is surrounded by a rim of erythema. Unlike syphilis, lesions are tender and the border of the ulcer is not indurated. Courtesy of Hon Pak, MD.

Chancroid is often referred to as a soft chancre because the lesions are usually not indurated. In contrast, a syphilitic chancre is nontender and indurated. The identification of the causative agent of chancroid was first reported in 1889 by August Ducrey, following experiments in which he autoinoculated patients' forearms with pus from their genital ulcers. [1, 2, 3}

Pathophysiology
H ducreyi produces a potent cytolethal distending toxin, which is an important virulence factor in the pathogenesis of chancroid, probably contributing to both the generation and the slow healing of ulcers.[4, 5, 6, 7] H ducreyi contains a fimbrialike protein (Flp) operon that encodes proteins that contribute to adherence and pathogenesis. The production and secretion of 3 Flp proteins, Flp1, Flp2, Flp3, has been demonstrated to contribute to microcolony formation and attachment to human foreskin fibroblasts cells in vitro.[8} In a small human trial, injection of a deletion mutant that lacked expression of all 3 Flp proteins into volunteers demonstrated significantly reduced size of papule formation, as well as pustule formation rate.[9] Chancroid, or soft chancre, facilitates human immunodeficiency virus (HIV) transmission. The chemokine receptors CCR5 and CXCR4 belong to the class of 7 transmembrane G-proteincoupled receptors, and their natural ligands are key players in the recruitment of immune cells to sites of inflammation. CCR5 and CXCR4 are the 2 main co-receptors essential for HIV entry. Macrophages in chancroid lesions have significantly increased expression of CCR5 and CXCR4 compared with peripheral blood cells, and CD4 T cells have significant up-regulation of CCR5. The beta-chemokine RANTES (regulated on activation, normal T cell expressed and secreted) are important ligands for CCR5. RANTES is present throughout the papular and pustular stages of chancroid infection but is not present in uninfected control skin.[10] Together with the disruption of mucosal and skin barriers, the presence of cells with up-regulated HIV1 co-receptors in H ducreyi infected lesions provides an environment that facilitates the acquisition of HIV-1 infection. Effective and early treatment of genital ulceration, and chancroid in particular, may help to control the spread of HIV infection in tropical countries [11} ; however, at present, evidence to determine whether this will significantly reduce the risk of HIV acquisition is insufficient. [12, 13]

Epidemiology

Frequency
United States Chancroid is rarely reported in the United States, but regional outbreaks and some endemic transmission occur, principally among migrant farm workers and poor inner-city residents. [14] International Because of a lack of readily available, accurate diagnostic tests, the global incidence of chancroid is unknown. An estimated 6 million cases of chancroid occur each year. Chancroid is common in many of the world's poorest regions such as areas of Africa, Asia, and the Caribbean. These regions also have some of the highest rates of HIV infection in the world, and chancroid is common in all 18 countries where adult HIV prevalence surpasses 8%. In addition to regional outbreaks, individual cases are reported sporadically in the developed world, usually in individuals who have recently returned from chancroid-endemic areas or occasionally within the context of localized urban outbreaks, which may be associated with commercial sex work.

Mortality/Morbidity
Chancroid produces painful ulcers on the genitals, often (50%) associated with unilateral tender inguinal lymphadenitis (ie, a bubo). Left untreated, the buboes can form fluctuant abscesses that spontaneously rupture, resulting in a nonhealing ulcer. Chancroid has been shown to be a major cofactor in the transmission of HIV-1 infection. [15] This relationship has been especially significant in the heterosexual spread of HIV in Africa. [11, 16]

Sex
Males develop chancroid most often, with a male-to-female ratio of 3-25:1. [17]Uncircumcised men develop chancroid more often than circumcised men.[18]Patients who are uncircumcised do not respond to treatment as well as those who are circumcised.[19, 20] Chancroid is more common in heterosexual men.[21] Female prostitutes, either with active disease in the form of genital ulcers or as asymptomatic carriers, are an important reservoir for chancroid infection.

Age
Chancroid is most prevalent in sexually active and promiscuous males, with a mean patient age of 30 years.

History
After an incubation period of 3-7 days, the patient develops painful, erythematous papules at the site of contact. The chancroid papules become pustular and then rupture, usually forming 1-3 painful ulcers. Men usually have chancroid symptoms directly related to the painful genital lesions or inguinal tenderness. Most females are asymptomatic but may present with less obvious symptoms, such as dysuria, dyspareunia, vaginal discharge, pain on defecation, or rectal bleeding. Constitutional symptoms of chancroid, such as malaise and low-grade fevers, may be present. Most commonly, males with chancroid report a history of recent contact with a prostitute. In addition, men who are infected are less likely to have used condoms and more likely to report a history of more than 2 sexual partners in the preceding 3 months. Oral sex has also been documented in the transmission of chancroid. Reports of nonsexually transmitted H ducreyi infection have also been described, most recently from Australia in expatriates visiting from Papua New Guinea and Vanuatu. Infection led to chronic lowerlimb ulcers.[22]

Physical
With chancroid, a small papule is the initial lesion at the site of infection. The papule rapidly becomes pustular and eventually ulcerates. The ulcer enlarges, develops ragged undermined borders, and is surrounded by a rim of erythema. The border of the chancroid ulcer is not indurated as in syphilis. A grayish fibrinous membrane covers the base of the ulcer. Autoinoculation results in multiple sites of infection in various stages of evolution. In men, the most common site of the chancroid infection is the foreskin, but it may also occur less commonly on the shaft, the glans, or the meatus of the penis. In women, chancroid ulcers most commonly occur on the labia majora, but they may also occur on the labia minora, the thighs, the perineum, or the cervix. As many as 50% of chancroid patients have tender, fixed, inguinal lymphadenopathy, usually unilaterally, that when fluctuant is called a bubo and is highly specific for chancroid, as seen in the images below.

This patient shows the characteristic lesions of chancroid. The bubo on the right side drained spontaneously. The bubo in the left inguinal canal required needle aspiration.

Close-up view of chancroid ulcers.v

A probable chancroid diagnosis can be made if all the following criteria are met [23, 24, 25] : The patient has one or more painful genital ulcers. The patient has no evidence of Treponema pallidum infection by darkfield examination of ulcer exudate or by serologic testing for syphilis performed at least 7 days after the onset of ulcers. The clinical presentation, the appearance of genital ulcers, and, if present, the presence of regional lymphadenopathy are typical for chancroid. Test results for herpes simplex virus (HSV) performed on the ulcer exudate are negative.[26] The combination of a painful ulcer and tender inguinal adenopathy, symptoms occurring in one third of patients, suggests a diagnosis of chancroid; when accompanied by suppurative inguinal adenopathy, these signs are almost pathognomonic.

Causes
H ducreyi (a short gram-negative bacillus) causes chancroid. See Pathophysiology. Chancroid is closely associated with prostitution. H ducreyi can survive only in subgroups of the population with a sufficient turnover of sex partners. Chancroid is not a sustainable infection in sexual networks with low rates of partner change.

Differential Diagnoses
Behcet Disease

Fixed Drug Eruptions Herpes Simplex Lymphogranuloma Venereum Syphilis

Laboratory Studies
The diagnosis of chancroid based solely on the ulcer's appearance is accurate only in 30-50% of cases. In areas of high prevalence, the accuracy for a clinical diagnosis of chancroid is as high as 80%; however, in areas where the disease is less common, the clinical basis for diagnosing chancroid leads to overdiagnosis. Considerable overlap exists between the major causes of GUD: herpes simplex, syphilis, chancroid, and, often, co-infection with 2 diseases at the same time. Co-infection with syphilis or HSV occurs in as many as 10% of patients. Realizing that no etiology can be found in 25-50% of all cases of GUD is important. Gram staining may show gram-negative coccobacilli singly, in clusters, or in various morphological forms described as "schools of fish," "railroad tracks," or "fingerprints." The organisms are visualized extracellularly more often than intracellularly and tend to occur in close proximity to polymorphonuclear leukocytes. Gram staining of an ulcer specimen is not highly specific or sensitive. Interpretation is hampered by polymicrobial contamination. However, slides with gram-negative coccobacilli in parallel rows or in a clustered school-of-fish pattern have been reported to have a sensitivity of 62% and a specificity of 99% for chancroid. Direct microscopy should not be used in the routine diagnosis of chancroid. Culture is now the accepted standard for chancroid diagnosis in most areas, but even in an experienced laboratory, it is only 60-80% sensitive. Numerous selective artificial media have been developed, but 2 media are commonly used. Nairobi medium consists of a biplate of (1) gonococcal agar base with 2% bovine hemoglobin and 5% fetal calf serum and (2) Mueller-Hinton agar with 5% chocolatized horse blood. Both media contain vancomycin (3 mcg/mL) and 1% CVA (ie, cephalothin, vancomycin, and amphotericin B) enrichment. The use of both media together increases the yield of positive cultures. Most H ducreyiorganisms are resistant to vancomycin, but some strains are inhibited by its presence. Therefore, negative culture results in the setting of high suspicion should prompt screening for vancomycin-sensitive organisms.[27] A simple, inexpensive medium containing gonococcal agar base supplemented with 5% Fildes' extract and unchocolatized horse blood or a medium containing 0.2% activated charcoal instead of fetal calf serum is a suitable alternative for diagnostic purposes in resource-poor countries. H ducreyi is a fastidious organism. Patients' specimens must either be plated out directly on an appropriate culture medium or sent to the microbiology laboratory for culture as soon as possible. No widely available transport medium exists.[28] Studies have shown cultures to be less sensitive in women than in men. Purulent material aspirated from intact buboes is almost always sterile. Polymerase chain reaction (PCR) amplification is replacing culture as the diagnostic test of choice in some major medical centers. PCR amplification using a variety of primers may provide a useful alternative to culture for the detection of H ducreyi. Although PCR assays perform well on samples prepared from H ducreyicultures, they are less sensitive when used to test genital ulcer specimens. [29] A multiplex PCR assay has been developed for the simultaneous amplification of DNA targets from H ducreyi, T pallidum, and HSV types 1 and 2 and appears more sensitive than standard diagnostic tests for the detection of these etiologic agents in genital ulcer specimens. The multiplex PCR assay has been developed but is not yet commercially available. [30, 31] Monoclonal antibodybased technology has the potential to provide a simple, inexpensive, rapid, and sensitive means of detecting H ducreyi in genital ulcer specimens, but no assay kits are commercially available.[29] Serology has limited usefulness in the routine diagnosis of chancroid infection.

Tissue biopsy is not a recommended diagnostic method for chancroid but may be useful as a means to exclude malignancy in nonhealing or atypical ulcers. Serologic tests for syphilis include the Venereal Disease Research Laboratory (VDRL) test, rapid plasma reagin (RPR) test, and a darkfield examination. Tests for HSV include a Tzanck smear, direct fluorescence microscopy, and culture. HIV testing should be performed in all patients who have genital ulcers caused by H ducreyi. Patients should be retested for syphilis and HIV 3 months after the diagnosis of chancroid if the initial test results were negative. Consider tests for other sexually transmitted diseases (STDs), including hepatitis B, Chlamydia trachomatis infection, and gonorrhea. As PCR and other techniques become available, cultures may be indicated to obtain a specimen for antibiotic sensitivity testing.

Histologic Findings
Histologic features from a biopsy sample of a chancroid ulcer overlap significantly with those of syphilitic chancres. Lesions show 3 zones. The most superficial zone is narrow and consists of neutrophils, fibrin, erythrocytes, and necrotic tissue. The second zone is wider and contains newly formed blood vessels with marked endothelial cell proliferation. The lumina of many of these vessels are occluded, leading to thrombosis. The deepest zone is composed of a dense infiltrate of plasma cells and lymphoid cells. H ducreyi bacilli are seldom demonstrable on biopsy samples. Tissue biopsy is not a recommended diagnostic method for chancroid but may be useful as a means to exclude malignancy in nonhealing or atypical ulcers.

Medical Care
Local therapy for chancroid includes gentle topical cleansing, soaks, and measures to reduce edema. Patients with nonfluctuant buboes respond well to antibiotics, and the chancroid lesions do not need to be drained. If appropriate chancroid therapy is provided and no clinical improvement is evident, the clinician must consider whether the diagnosis is correct, whether the patient is co-infected with another STD, whether the patient is infected with HIV, whether the treatment instructions were followed properly, and whether the H ducreyi strain is resistant to the prescribed antimicrobial. In resource-poor settings, where diagnostic facilities are not readily available, the World Health Organization advocates the use of a syndromic approach for the therapy of GUD. [23, 24, 32, 33] The syndromic approach for the therapy of STDs delivers effective treatment quickly to people when they first come in for care and is focused on the most common STDs that can be cured, including syphilis, gonorrhea, chlamydia, chancroid, trichomoniasis, and candidiasis. The syndromic approach does not require the use of expensive tests, which often are not available. People who may have more than one STD infection are treated with the most effective drug available. In some undeveloped regions, 6 of every 10 patients with an STD have 2 or more different infections at the same time. This approach also emphasizes treatment during the first visit. Treating curable STDs as soon as possible limits the future spread of STDs, including HIV. STD syndromes that cause similar signs and symptoms are included in a simple flow chart to help health care workers use the syndromic approach to make a diagnosis and begin appropriate therapy. Using the syndromic approach is as follows: Men who present with a urethral discharge are treated for both gonorrhea and chlamydia.

Women who present with lower abdominal pain are treated for gonorrhea, chlamydia, and other bacterial infections. Women who present with vaginal discharge and cervicitis are treated for gonorrhea and chlamydia. Women who present with vaginal discharge and vaginitis are treated for trichomoniasis and candidiasis. Men or women who present with genital ulcers are treated for syphilis, chancroid, and genital herpes. Treating people with STDs in this way is less expensive long term because more people are cured the first time they come for care and because the spread of STD may be limited. The recommended drugs for STDs should be selected based on cost, availability, and local resistance patterns.[34, 35] A proper supply of STD drugs and training programs for health care workers are essential. With the syndromic approach, less emphasis is placed on identifying the cause of a particular STD. This may be difficult for some health care workers to accept when they have been trained to identify the specific cause of a disease before starting therapy. However, in a setting where rapid therapy is of utmost importance and sophisticated laboratories are not available, the syndromic approach provides effective treatment. Prompt, effective therapy and education of patients helps them decide to use condoms, change their risky sexual behavior, and convince their partner to seek treatment.

Surgical Care
Fluctuant buboes should be drained with the patient under local anesthesia. Insert a large-gauge needle into the bubo, passing through normal tissue from the side or the top of the lesion rather than the bottom, thus avoiding continuous dependent drainage and fistula formation, as demonstrated in the image below.

Large fluctuant buboes should be drained with the patient under local anesthesia and a large-gauge needle inserted through surrounding healthy skin. The insertion site should be superior or lateral to the bubo to prevent chronic drainage from the site.

Incision and drainage is an effective method for treating fluctuant buboes and may be preferable to traditional needle aspiration, considering the frequency of required repeat aspirations in some studies.
[36]

If circumcision is needed, it should be completed after the patient successfully completes treatment with antibiotics.

Activity

Patients should refrain from sexual activity until ulcers are healed. Untreated chancroid ulcers may persist for 1-3 months. Chancroid ulcers treated with the appropriate antibiotic agent resolve within 714 days.

Medication Summary
Guidelines for therapy are usually based on the presenting symptoms and the clinical distribution of infection. Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Successful treatment for chancroid cures the infection, resolves the clinical symptoms, and prevents chancroid transmission to others. The US Centers for Disease Control and Prevention (CDC) recommends any one of the following treatments for chancroid: Azithromycin 1 g orally in a single dose Ceftriaxone 250 mg intramuscularly in a single dose Ciprofloxacin 500 mg orally twice a day for 3 days Erythromycin base 500 mg 3 times a day for 7 days Ciprofloxacin is contraindicated for pregnant and lactating women. Azithromycin and ceftriaxone offer the advantage of single-dose therapy.[37] Worldwide, several isolates with intermediate resistance to either ciprofloxacin or erythromycin have been reported. [32, 38] A 2009 study of 54 subjects from Brazil suggests that single-dose therapy with thiamphenicol (89% cure rate) is more effective than single-dose therapy with azithromycin (73% cure rate). However, HIV seropositivity was associated with treatment failures. Notably, all HIV-positive subjects treated with azithromycin had treatment failure, prompting the authors to recommend avoiding azithromycin in HIV-coinfected patients.[39] Uncircumcised men and patients who are infected with HIV do not respond to therapy as well as others. Chancroid relapses after antibiotic therapy in as many as 5% of patients, and relapses are more common in patients who are uncircumcised or are infected with HIV. If they are not infected with HIV, repeating the original therapy is usually effective. Because chancroid treatment is often accompanied by treatment for gonococcal infections, it is important to be aware of changes to the CDC guidelines for STDs. In December of 2010, the CDC updated treatment guidelines for sexually transmitted diseases. Of significance to the treatment of chancroid, it details the increasing prevalence of antimicrobial-resistant Neisseria gonorrhea, and that oral cephalosporins are no longer recommended for the treatment of gonorrhea. For more information see, the CDCs Antibiotic-Resistant Gonorrhea Web site.

Antibiotic, Other
The goal of pharmacotherapy for chancroid is to reduce morbidity and to prevent complications.

Ceftriaxone (Rocephin)
Ceftriaxone is a third-generation cephalosporin with broad-spectrum, gram-negative activity; it has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. It arrests bacterial growth by binding to 1 or more penicillin-binding proteins.

Azithromycin (Zithromax)
Azithromycin acts by binding to the 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected. Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest that its concentration in phagocytes may contribute to drug distribution to inflamed tissues.

Azithromycin treats mild-to-moderate microbial infections. Plasma concentrations are very low, but tissue concentrations are much higher, giving it value in treating intracellular organisms. It has a long tissue half-life.

Erythromycin (E-Mycin, Eryc, Ery-Tab)

The recommended dosing schedule for erythromycin may result in GI upset, causing one to prescribe an alternative macrolide or change to thrice-daily dosing. Erythromycin covers most potential etiologic agents, including Mycoplasmaspecies. It is less active against Haemophilus influenzae. Although 10 days seems to be a standard course of treatment, treating until the patient has been afebrile for 3-5 days seems more rational. It inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. It is ndicated for staphylococcal and streptococcal infections. In children, age, weight, and severity of infection determine proper dosage. When twice-daily dosing is desired, half the total daily dose may be taken q12h. For more severe infections, double the dose. Erythromycin has the added advantage of being a good anti-inflammatory agent by inhibiting migration of polymorphonuclear leukocytes.

Ciprofloxacin (Cipro)
Ciprofloxacin is a fluoroquinolone that inhibits bacterial DNA synthesis and, consequently, growth, by inhibiting DNA gyrase and topoisomerases, which are required for replication, transcription, and translation of genetic material. Quinolones have broad activity against gram-positive and gramnegative aerobic organisms. Ciprofloxacin has no activity against anaerobes. Continue treatment for at least 2 days (7-14 d typical) after signs and symptoms have disappeared.

Further Outpatient Care

Chancroid patients should receive follow-up care to ensure resolution of the disease. Clinical improvement of chancroid should occur over 7 days, and, with appropriate antibiotic therapy, healing should be complete in 2 weeks. Healing is slower for some uncircumcised men who have ulcers under the foreskin. Lymphadenopathy may be slow to resolve and may require needle aspiration if a significant bubo is present. Because of the highly infectious nature of chancroid, routine treatment of contacts of men with chancroid is recommended even if they are asymptomatic. All sexual contacts during the 10 days prior to the development of the genital lesion should be treated. Empirical chancroid treatment of high-risk women has been shown to significantly decrease the prevalence of disease. Isolation or quarantine is not required for chancroid, but patients must avoid sexual contact until all lesions, including discharging regional lymph nodes, are healed.

Deterrence/Prevention
Eradication of chancroid is a feasible public health objective. H ducreyi has a short duration of infectivity and requires frequent contacts to spread within a population. Humans are the only reservoir for H ducreyi, and rates of infection can be easily reduced through a variety of methods. Simple washing with soap and water within a few hours of sexual exposure is effective in reducing the risk of contracting chancroid.[40] Male circumcision is also moderately protective against H ducreyi.[19] Instituting a condom policy directed at protecting sex workers and their clients from exposure to STDs and improving curative services are among the most effective strategies. Offering regular examinations and treatment for registered sex workers or monthly presumptive antibiotic treatment to women at risk have both been shown to dramatically reduce the prevalence of

chancroid. Antibiotic treatment of the highest-risk populations can reduce chancroid transmission in the short term and can lead to a rapid decline in chancroid prevalence in a community. Breaking the chancroid transmission cycle in any of these ways can markedly reduce the prevalence of chancroid, even when other conditions favor its spread. [18, 41]

Complications
Phimosis, balanoposthitis, and rupture of buboes with fistula formation and scarring are reported complications of chancroid.

Prognosis
The prognosis is excellent if chancroid is treated properly and if no co-infection with HIV is present. As many as 5% of patients have a chancroid relapse and usually respond to a repeat course of their original therapy. No adverse effects of chancroid on pregnancy outcome have been reported. Chancroid-infected patients who have HIV should be monitored closely because they are more likely to experience treatment failure and to have ulcers that heal slowly.

Patient Education
The patient should be strongly advised to avoid sexual contacts while the ulcers are open because they are highly infectious and may cause a community outbreak. Patients should be advised to avoid prostitutes, to use condoms, and to avoid having multiple partners. Cocaine and alcohol abuse should be addressed because both contribute to higher rates of the disease. For patient education resources, see the Men's Health Center and Sexually Transmitted Diseases Center, as well as Sexually Transmitted Diseases, Birth Control Overview, and Birth Control FAQs.